Bioinformatically detectable group of novel viral regulatory genes and uses thereof

ABSTRACT

The present invention relates to a group of novel viral RNA regulatory genes, here identified as “viral genomic address messenger genes” or “VGAM genes”, and as “genomic address genes” or “GR” genes. VGAM genes selectively inhibit translation of known host target genes, and are believed to represent a novel pervasive viral attack mechanism. GR genes encode an operon-like cluster of VGAM genes. VGAM and viral GR genes may therefore be useful in diagnosing, preventing and treating viral disease. Several nucleic acid molecules are provided respectively encoding several VGAM genes, as are vectors and probes both comprising the nucleic acid molecules, and methods and systems for detecting VGAM genes, and for counteracting their activity.

FIELD OF THE INVENTION

The present invention relates to a group of bioinformatically detectable novel viral RNA regulatory genes, here identified as “viral genomic address messenger” or “VGAM” genes.

BACKGROUND OF THE INVENTION

Small RNAs are known to perform diverse cellular functions, including post-transcriptional gene expression regulation. The first two such RNA genes, Lin-4 and Let-7, were identified by genetic analysis of Caenorhabditis Elegans (Elegans) developmental timing, and were termed short temporal RNA (stRNA) (Wightman, B., Ha, I., Ruvkun, G., Cell 75, 855 (1993); Erdmann, V. A. et al., Nucleic Acids Res. 29, 189 (2001); Lee, R. C., Feinbaum, R. L., Ambros, V., Cell 75, 843 (1993); Reinhart, B. et al., Nature 403, 901 (2000)).

Lin-4 and Let-7 each transcribe a ˜22 nucleotide (nt) RNA, which acts a post transcriptional repressor of target mRNAs, by binding to elements in the 3′-untranslated region (UTR) of these target mRNAs, which are complimentary to the 22 nt sequence of Lin-4 and Let-7 respectively. While Lin-4 and Let-7 are expressed at different developmental stage, first larval stage and fourth larval stage respectively, both specify the temporal progression of cell fates, by triggering post-transcriptional control over other genes (Wightman, B., Ha, I., Ruvkun, G., Cell 75, 855 (1993); Slack et al., Mol. Cell 5, 659 (2000)). Let-7 as well as its temporal regulation have been demonstrated to be conserved in all major groups of bilaterally symmetrical animals, from nematodes, through flies to humans (Pasquinelli, A., et al. Nature 408, 86 (2000)).

The initial transcription product of Lin-4 and Let-7 is a ˜60-80 nt RNA, the nucleotide sequence of the first half of which is partially complimentary to that of its second half, therefore allowing this RNA to fold onto itself, forming a ‘hairpin structure’. The final gene product is a ˜22 nt RNA, which is ‘diced’ from the above mentioned ‘hairpin structure’, by an enzyme called Dicer, which also apparently also mediates the complimentary binding of this ˜22 nt segment to a binding site in the 3′ UTR of its target gene.

Recent studies have uncovered 93 new genes in this class, now referred to as micro RNA or miRNA genes, in genomes of Elegans, Drosophilea, and Human (Lagos-Quintana, M., Rauhut, R., Lendeckel, W., Tuschl, T., Science 294, 853 (2001); Lau, N. C., Lim, L. P., Weinstein, E. G., Bartel, D. P., Science 294, 858 (2001); Lee, R. C., Ambros, V., Science 294, 862 (2001). Like the well studied Lin-4 and Let-7, all newly found MIR genes produce a ˜60-80 nt RNA having a nucleotide sequence capable of forming a ‘hairpin structure’. Expressions of the precursor ˜60-80 nt RNA and of the resulting diced ˜22 nt RNA of most of these newly discovered MIR genes have been detected.

Based on the striking homology of the newly discovered MIR genes to their well-studied predecessors Lin-4 and Let-7, the new MIR genes are believed to have a similar basic function as that of Lin-4 and Let-7: modulation of target genes by complimentary binding to the UTR of these target genes, with special emphasis on modulation of developmental control processes. This is despite the fact that the above-mentioned recent studies did not find target genes to which the newly discovered MIR genes complementarily bind. While existing evidence suggests that the number of regulatory RNA genes “may turn out to be very large, numbering in the hundreds or even thousands in each genome”, detecting such genes is challenging (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

The ability to detect novel RNA genes is limited by the methodologies used to detect such genes. All RNA genes identified so far either present a visibly discernable whole body phenotype, as do Lin-4 and Let-7 (Wightman et. al., Cell 75, 855 (1993); Reinhart et al., Nature 403, 901 (2000)), or produce significant enough quantities of RNA so as to be detected by the standard biochemical genomic techniques, as do the 93 recently detected miRNA genes. Since a limited number clones were sequenced by the researchers discovering these genes, 300 by Bartel and 100 by Tuschl (Bartel et. al., Science 294, 858 (2001); Tuschl et. al., Science 294, 853 (2001)), the RNA genes found can not be much rarer than 1% of all RNA genes. The recently detected miRNA genes therefore represent the more prevalent among the miRNA gene family.

Current methodology has therefore been unable to detect RNA genes which either do not present a visually discernable whole body phenotype, or are rare (e.g. rarer than 0.1% of all RNA genes), and therefore do not produce significant enough quantities of RNA so as to be detected by standard biochemical technique.

To date, miRNA have not been detected in viruses.

SUMMARY OF THE INVENTION

The present invention relates to a novel group of bioinformatically detectable, viral regulatory RNA genes, which repress expression of host target host genes, by means of complementary hybridization to binding sites in untranslated regions of these host target host genes. It is believed that this novel group of viral genes represent a pervasive viral mechanism of attacking hosts, and that therefore knowledge of this novel group of viral genes may be useful in preventing and treating viral diseases.

In various preferred embodiments, the present invention seeks to provide improved method and system for detection and prevention of viral disease, which is mediated by this group of novel viral genes.

Accordingly, the invention provides several substantially pure nucleic acids (e.g., genomic nucleic acid, cDNA or synthetic nucleic acid) each encoding a novel viral gene of the VGAM group of gene, vectors comprising the nucleic acids, probes comprising the nucleic acids, a method and system for selectively modulating translation of known ‘target’ genes utilizing the vectors, and a method and system for detecting expression of known ‘target’ genes utilizing the probe.

By “substantially pure nucleic acid” is meant nucleic acid that is free of the genes which, in the naturally-occurring genome of the organism from which the nucleic acid of the invention is derived, flank the genes discovered and isolated by the present invention. The term therefore includes, for example, a recombinant nucleic acid which is incorporated into a vector, into an autonomously replicating plasmid or virus, or into the genomic nucleic acid of a prokaryote or eukaryote at a site other than its natural site; or which exists as a separate molecule (e.g., a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. It also includes a recombinant nucleic acid which is part of a hybrid gene encoding additional polypeptide sequence.

“Inhibiting translation” is defined as the ability to prevent synthesis of a specific protein encoded by a respective gene, by means of inhibiting the translation of the mRNA of this gene. “Translation inhibiter site” is defined as the minimal nucleic acid sequence sufficient to inhibit translation.

There is thus provided in accordance with a preferred embodiment of the present invention a bioinformatically detectable novel viral gene encoding substantially pure nucleic acid wherein: RNA encoded by the bioinformatically detectable novel viral gene is about 18 to about 24 nucleotides in length, and originates from an RNA precursor, which RNA precursor is about 50 to about 120 nucleotides in length, a nucleotide sequence of a first half of the RNA precursor is a partial inversed-reversed sequence of a nucleotide sequence of a second half thereof, a nucleotide sequence of the RNA encoded by the novel viral gene is a partial inversed-reversed sequence of a nucleotide sequence of a binding site associated with at least one host target gene, and a function of the novel viral gene is bioinformatically deducible.

There is further provided in accordance with another preferred embodiment of the present invention a method for anti-viral treatment comprising neutralizing said RNA.

Further in accordance with a preferred embodiment of the present invention the neutralizing comprises: synthesizing a complementary nucleic acid molecule, a nucleic sequence of which complementary nucleic acid molecule is a partial inversed-reversed sequence of said RNA, and transfecting host cells with the complementary nucleic acid molecule, thereby complementarily binding said RNA.

Further in accordance with a preferred embodiment of the present invention the neutralizing comprises immunologically neutralizing.

There is still further provided in accordance with another preferred embodiment of the present invention a bioinformatically detectable novel viral gene encoding substantially pure nucleic acid wherein: RNA encoded by the bioninformatically detectable novel viral gene includes a plurality of RNA sections, each of the RNA sections being about 50 to about 120 nucleotides in length, and including an RNA segment, which RNA segment is about 18 to about 24 nucleotides in length, a nucleotide sequence of a first half of each of the RNA sections encoded by the novel viral gene is a partial inversed-reversed sequence of nucleotide sequence of a second half thereof, a nucleotide sequence of each of the RNA segments encoded by the novel viral gene is a partial inversed-reversed sequence of the nucleotide sequence of a binding site associated with at least one target host gene, and a function of the novel viral gene is bioinformatically deducible from the following data elements: the nucleotide sequence of the RNA encoded by the novel viral gene, a nucleotide sequence of the at least one target host gene, and function of the at least one target host gene.

Further in accordance with a preferred embodiment of the present invention the function of the novel viral gene is bioinformatically deducible from the following data elements: the nucleotide sequence of the RNA encoded by the bioinformatically detectable novel viral gene, a nucleotide sequence of the at least one target host gene, and a function of the at least one target host gene.

Still further in accordance with a preferred embodiment of the present invention the RNA encoded by the novel viral gene complementarily binds the binding site associated with the at least one target host gene, thereby modulating expression of the at least one target host gene.

Additionally in accordance with a preferred embodiment of the present invention the binding site associated with at least one target host gene is located in an untranslated region of RNA encoded by the at least one target host gene.

Moreover in accordance with a preferred embodiment of the present invention the function of the novel viral gene is selective inhibition of translation of the at least one target host gene, which selective inhibition includes complementary hybridization of the RNA encoded by the novel viral gene to the binding site.

Further in accordance with a preferred embodiment of the present invention the invention includes a vector including the DNA.

Still further in accordance with a preferred embodiment of the present invention the invention includes a method of selectively inhibiting translation of at least one gene, including introducing the vector.

Moreover in accordance with a preferred embodiment of the present invention the introducing includes utilizing RNAi pathway.

Additionally in accordance with a preferred embodiment of the present invention the invention includes a gene expression inhibition system including: the vector, and a vector inserter, functional to insert the vector into a cell, thereby selectively inhibiting translation of at least one gene.

Further in accordance with a preferred embodiment of the present invention the invention includes a probe including the DNA.

Still further in accordance with a preferred embodiment of the present invention the invention includes a method of selectively detecting expression of at least one gene, including using the probe.

Additionally in accordance with a preferred embodiment of the present invention the invention includes a gene expression detection system including: the probe, and a gene expression detector functional to selectively detect expression of at least one gene.

Further in accordance with a preferred embodiment of the present invention the invention includes an anti-viral substance capable of neutralizing the RNA.

Still further in accordance with a preferred embodiment of the present invention the neutralizing includes complementarily binding the RNA.

Additionally, in accordance with a preferred embodiment of the present invention the neutralizing includes immunologically neutralizing.

Moreover in accordance with a preferred embodiment of the present invention the invention includes a method for anti-viral treatment including neutralizing the RNA.

Further in accordance with a preferred embodiment of the present invention the neutralizing includes: synthesizing a complementary nucleic acid molecule, a nucleic sequence of which complementary nucleic acid molecule is a partial inversed-reversed sequence of the RNA, and transfecting host cells with the complementary nucleic acid molecule, thereby complementarily binding the RNA.

Still further in accordance with a preferred embodiment of the present invention the neutralizing includes immunologically neutralizing.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a simplified diagram illustrating a mode by which viral genes of a novel group of viral genes of the present invention, modulate expression of known host target genes;

FIG. 2 is a simplified block diagram illustrating a bioinformatic gene detection system capable of detecting genes of the novel group of genes of the present invention, which system is constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 3 is a simplified flowchart illustrating operation of a mechanism for training of a computer system to recognize the novel genes of the present invention, which mechanism is constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 4A is a simplified block diagram of a non-coding genomic sequence detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 4B is a simplified flowchart illustrating operation of a non-coding genomic sequence detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 5A is a simplified block diagram of a hairpin detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 5B is a simplified flowchart illustrating operation of a hairpin detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 6A is a simplified block diagram of a dicer-cut location detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 6B is a simplified flowchart illustrating training of a dicer-cut location detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 7A is a simplified block diagram of a target-gene binding-site detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 7B is a simplified flowchart illustrating operation of a target-gene binding-site detector constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 8 is a simplified flowchart illustrating operation of a function & utility analyzer constructed and operative in accordance with a preferred embodiment of the present invention;

FIG. 9 is a simplified diagram describing a novel bioinformatically detected group of regulatory genes, referred to here as Genomic Record (GR) genes, each of which encodes an ‘operon-like’ cluster of novel miRNA-like genes, which in turn modulates expression of a plurality of target genes;

FIG. 10 is a block diagram illustrating different utilities of genes of a novel group of genes, and operons of a novel group of operons, both of the present invention;

FIGS. 11A and 11B are simplified diagrams, which when taken together illustrate a mode of gene therapy applicable to genes of the novel group of genes of the present invention;

FIG. 12A is an annotated sequence of EST72223 comprising novel gene GAM24 detected by the gene detection system of the present invention;

FIGS. 12B and 12C are pictures of laboratory results, which when taken together demonstrate laboratory confirmation of expression of the bioinformatically detected novel gene GAM24 of FIG. 12A;

FIG. 12D provides pictures of laboratory results, which when taken together demonstrate further laboratory confirmation of expression of the bioinformatically detected novel gene GAM24 of FIG. 12A;

FIG. 13A is an annotated sequence of an EST7929020 comprising novel genes GAM23 and GAM25 detected by the gene detection system of the present invention;

FIG. 13B is a picture of laboratory results, which confirm expression of bioinformatically detected novel genes GAM23 and GAM25 of FIG. 13A;

FIG. 13C is a picture of laboratory results, which confirm endogenous expression of bioinformatically detected novel gene GAM25 of FIG. 15A;

FIG. 14A is an annotated sequence of an EST1388749 comprising novel gene GAM26 detected by the gene detection system of the present invention;

FIG. 14B is a picture of laboratory results, which confirm expression of the bioinformatically detected novel gene GAM26 of FIG. 14A;

FIGS. 15A through 1000D are schematic diagrams illustrating sequences, functions and utilities of 986 specific viral genes of the novel group of viral regulatory genes of the present invention, detected using the bioinformatic gene detection system described hereinabove with reference to FIGS. 1 through 8; and

FIGS. 3088 through 3308 are schematic diagrams illustrating sequences, functions and utilities of 221 specific viral genes of a group of novel regulatory ‘operon-like’ viral genes of the present invention, detected using the bioinformatic gene detection system described hereinabove with reference to FIGS. 9 through 14.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

Reference is now made to FIG. 1 which is a simplified diagram illustrating a mode by which genes of a novel group of genes of the present invention, modulate expression of known host target.

The novel genes of the present invention are micro RNA (miRNA)-like, regulatory RNA genes, modulating expression of known host target. This mode of modulation is common to other known miRNA genes, as described hereinabove with reference to the background of the invention section.

VGAM GENE and TARGET GENE are two human genes contained in the DNA of the human genome.

VGAM GENE encodes a VGAM PRECURSOR RNA. However, similar to other miRNA genes, and unlike most ordinary genes, its RNA, VGAM PRECURSOR RNA, does not encode a protein.

VGAM PRECURSOR RNA folds onto itself, forming VGAM FOLDED PRECURSOR RNA. As FIG. 8 illustrates, VGAM FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical genes of the miRNA genes, and is due to the fact that nucleotide sequence of the first half of the RNA of a gene in this group is an accurate or partial inversed-reversed sequence of the nucleotide sequence of its second half. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex, designated DICER COMPLEX, ‘dices’ the VGAM FOLDED PRECURSOR RNA into a single stranded RNA segment, about 22 nucleotides long, designated VGAM RNA. As is known in the art, ‘dicing’ of the hairpin structured RNA precursor into shorter RNA segments about 22 nucleotides long by a Dicer type enzyme is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

TARGET GENE encodes a corresponding messenger RNA, designated TARGET RNA. This TARGET RNA comprises 3 regions: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM RNA binds complementarily a BINDING SITE, located on the 3′UTR segment of TARGET RNA. This complementarily binding is due to the fact that the nucleotide sequence of VGAM RNA is an accurate or partial inversed-reversed sequence of the nucleotide sequence of BINDING SITE.

The complimentary binding of VGAM RNA to BINDING SITE inhibits translation of TARGET RNA into TARGET PROTEIN. TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated by one skilled in the art that the mode of transcriptional inhibition illustrated by FIG. 1 with specific reference to VGAM genes of the present invention, is in fact common to all other miRNA genes. A specific complimentary binding site has been demonstrated only for Lin-4 and Let-7. All the other 93 newly discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites for these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)). The present invention discloses a novel group of genes, the VGAM genes, belonging to the miRNA genes group, and for which a specific an complimentary binding has been determined.

Reference is now made to FIG. 2 which is a simplified block diagram illustrating a bioinformatic gene detection system capable of detecting genes of the novel group of genes of the present invention, which system is constructed and operative in accordance with a preferred embodiment of the present invention.

A centerpiece of the present invention is a bioinformatic gene detection engine 100, which is a preferred implementation of a mechanism capable of bioinformatically detecting genes of the novel group of genes of the present invention.

The function of the bioinformatic gene detection engine 100 is as follows: it receives three types of input, expressed RNA data 102, sequenced DNA data 104, and protein function data 106, performs a complex process of analysis of this data as elaborated below, and based on this analysis produces output of a bioinformatically detected group of novel genes designated 108.

Expressed RNA data 102 comprises published expressed sequence tags (EST) data, mRNA data, as well as other sources of published RNA data. Sequenced DNA data 104 comprises alphanumeric data describing sequenced genomic data, which preferably includes annotation data such as location of known protein coding regions relative to the sequenced data. Protein function data 106 comprises scientific publications reporting studies which elucidated physiological function known proteins, and their connection, involvement and possible utility in treatment and diagnosis of various diseases. Expressed RNA data 102, sequenced DNA data 104 may preferably be obtained from data published by the National Center for Bioinformatics (NCBI) at the National Institute of Health (NIH), as well as from various other published data sources. Protein function data 106 may preferably be obtained from any one of numerous relevant published data sources, such as the Online Mendelian Inherited Disease In Man (OMIM) database developed by John Hopkins University, and also published by NCBI.

Prior to actual detection of bioinformatically detected novel genes 108 by the bioinformatic gene detection engine 100, a process of bioinformatic gene detection engine training & validation designated 110 takes place. This process uses the known miRNA genes as a training set (some 200 such genes have been found to date using biological laboratory means), to train the bioinformatic gene detection engine 100 to bioinformatically recognize miRNA-like genes, and their respective potential target binding sites. Bioinformatic gene detection engine training & validation 110 is further describe hereinbelow with reference to FIG. 3.

The bioinformatic gene detection engine 100 comprises several modules which are preferably activated sequentially, and are described as follows:

A non-coding genomic sequence detector 112 operative to bioinformatically detect non-protein coding genomic sequences. The non-coding genomic sequence detector 112 is further described hereinbelow with reference to FIGS. 4A and 4B.

A hairpin detector 114 operative to bioinformatically detect genomic ‘hairpin-shaped’ sequences, similar to VGAM FOLDED PRECURSOR of FIG. 1. The hairpin detector 114 is further described hereinbelow with reference to FIGS. 5A and 5B.

A dicer-cut location detector 116 operative to bioinformatically detect the location on a hairpin shaped sequence which is enzymatically cut by DICER COMPLEX of FIG. 1. The dicer-cut location detector 116 is further described hereinbelow with reference to FIG. 6A.

A target-gene binding-site detector 118 operative to bioinformatically detect host target having binding sites, the nucleotide sequence of which is partially complementary to that of a given genomic sequence, such as a sequence cut by DICER COMPLEX of FIG. 1. The target-gene binding-site detector 118 is further described hereinbelow with reference to FIGS. 7A and 7B.

A function & utility analyzer 120 operative to analyze function and utility of host target, in order to identify host target which have a significant clinical function and utility. The function & utility analyzer 120 is further described hereinbelow with reference to FIG. 8.

Hardware implementation of the bioinformatic gene detection engine 100 is important, since significant computing power is preferably required in order to perform the computation of bioinformatic gene detection engine 100 in reasonable time and cost. As an example, it is estimated that using one powerful 8-processor PC Server, over 30 months of computing time (at 24 hours per day) would be required in order to detect all miRNA genes in human EST data, and their respective binding sites.

For example, in order to address this challenge at reasonable time and cost, a preferred embodiment of the present invention may comprise a cluster of a large number of personal computers (PCs), such as 100 PCs (Pentium IV, 1.7 GHz, with 40 GB storage each), connected by Ethernet to several strong servers, such as 4 servers (2-CPU, Xeon 2.2 GHz, with 200 GB storage each), combined with an 8-processor server (8-CPU, Xeon 550 Mhz w/8 GB RAM) connected via 2 HBA fiber-channels to an EMC Clariion 100-disks, 3.6 Terabyte storage device. Additionally, preferably an efficient database computer program, such as Microsoft™ SQL-Server database computer program is used and is optimized to the specific requirements of bioinformatic gene detection engine 100. Furthermore, the PCs are preferably optimized to operate close to 100% CPU usage continuously, as is known in the art. Using suitable hardware and software may preferably reduce the required calculation time in the abovementioned example from 30 months to 20 days.

It is appreciated that the abovementioned hardware configuration is not meant to be limiting, and is given as an illustration only. The present invention may be implemented in a wide variety of hardware and software configurations.

The present invention discloses 3815 novel viral genes of the VGAM group of genes, which have been detected bioinformatically, as described hereinbelow with reference to FIGS. 15 through 3829. Laboratory confirmation of 4 genes of the GAM group of genes is described hereinbelow with reference to FIGS. 7A through 16.

Reference is now made to FIG. 3 which is a simplified flowchart illustrating operation of a mechanism for training of a computer system to recognize the novel genes of the present invention. This mechanism is a preferred implementation of the bioinformatic gene detection engine training & validation 110 described hereinabove with reference to FIG. 2.

Bioinformatic gene detection engine training & validation 110 of FIG. 2 begins by training the bioinformatic gene detection engine to recognize known miRNA genes, as designated by numeral 122. This training step comprises hairpin detector training & validation 124, further described hereinbelow with reference to FIG. 12 A, dicer-cut location detector training & validation 126, further described hereinbelow with reference to FIGS. 6A and 6B, and target-gene binding-site detector training & validation 128, further described hereinbelow with reference to FIG. 7A.

Next, the bioinformatic gene detection engine 100 is used to bioinformatically detect sample novel genes, as designated by numeral 130. An example of a sample novel gene thus detected is described hereinbelow with reference to FIG. 12.

Finally, wet lab experiments are preferably conducted in order to validate expression and preferably function the sample novel genes detected by the bioinformatic gene detection engine 100 in the previous step. An example of wet-lab validation of the above-mentioned sample novel gene bioinformatically detected by the system is described hereinbelow with reference to FIGS. 13A and 13B.

Reference is now made to FIG. 4A which is a simplified block diagram of a preferred implementation of the non-coding genomic sequence detector 112 described hereinabove with reference to FIG. 2. Non-protein coding genomic sequence detector 112 of FIG. 2 preferably receives as input at least two types of published genomic data: expressed RNA data 102, including EST data and mRNA data, and sequenced DNA data 104. After its initial training, indicated by numeral 134, and based on the abovementioned input data, the non-protein coding genomic sequence detector 112 produces as output a plurality of non-protein coding genomic sequences 136. Preferred operation of the non-protein coding genomic sequence detector 112 is described hereinbelow with reference to FIG. 4B.

Reference is now made to FIG. 4B which is a simplified flowchart illustrating a preferred operation of the non-coding genomic sequence detector 112 of FIG. 2. Detection of non-protein coding genomic sequences to be further analyzed by the system generally preferably progresses in one of the following two paths.

A first path for detecting non-protein coding genomic sequences begins by receiving a plurality of known RNA sequences, such as EST data. Each RNA sequence is first compared to all known protein-coding sequences, in order to select only those RNA sequences which are non-protein coding. This can preferably be performed by BLAST comparison of the RNA sequence to known protein coding sequences. The above-mentioned BLAST comparison to the DNA preferably also provides the localization of the RNA on the DNA.

Optionally, an attempt may be made to ‘expand’ the non-protein RNA sequences thus found, by searching for transcription start and end signals, upstream and downstream of location of the RNA on the DNA respectively, as is well known in the art.

A second path for detecting non-protein coding genomic sequences starts by receiving DNA sequences. The DNA sequences are parsed into non protein coding sequences, based on published DNA annotation data: extracting those DNA sequences which are between known protein coding sequences. Next, transcription start and end signals are sought. If such signals are found, and depending on their ‘strength’, probable expressed non-protein coding genomic sequences are yielded.

Reference is now made to FIG. 5A which is a simplified block diagram of a preferred implementation of the hairpin detector 114 described hereinabove with reference to FIG. 2.

The goal of the hairpin detector 114 is to detect ‘hairpin’ shaped genomic sequences, similar to those of known miRNA genes. As mentioned hereinabove with reference to FIG. 1, a ‘hairpin’ genomic sequence refers to a genomic sequence which ‘folds onto itself’ forming a hairpin like shape, due to the fact that nucleotide sequence of the first half of the nucleotide sequence is an accurate or

The hairpin detector 114 of FIG. 2 receives as input a plurality of non-protein coding genomic sequences 136 of FIG. 4A, and after a phase of hairpin detector training & validation 124 of FIG. 3, is operative to detect and output ‘hairpin shaped’ sequences found in the input expressed non-protein coding sequences, designated by numeral 138.

The phase of hairpin detector training & validation 124 is an iterative process of applying the hairpin detector 114 to known hairpin shaped miRNA genes, calibrating the hairpin detector 114 such that it identifies the training set of known hairpins, as well as sequences which are similar thereto. Preferred operation of the hairpin detector 114 is described hereinbelow with reference to FIG. 5B.

Reference is now made to FIG. 5B which is a simplified flowchart illustrating a preferred operation of the hairpin detector 114 of FIG. 2.

A hairpin structure is a two dimensional folding structure, resulting from the nucleotide sequence pattern: the nucleotide sequence of the first half of the hairpin sequence is an inversed-reversed sequence of the second half thereof. Different methodologies are known in the art for detection of various two dimensional and three dimensional hairpin structures.

In a preferred embodiment of the present invention, the hairpin detector 114 initially calculates possible 2-dimensional (2D) folding patterns of a given one of the non-protein coding genomic sequences 136, preferably using a 2D folding algorithm based on free-energy calculation, such as the Zucker algorithm, as is well known in the art.

Next, the hairpin detector 114 analyzes the results of the 2D folding, in order to determine the presence, and location of hairpin structures. A 2D folding algorithm typically provides as output a listing of the base-pairing of the 2D folded shape, i.e. a listing of which all two pairs of nucleotides in the sequence which will bond. The goal of this second step, is to assess this base-pairing listing, in order to determine if it describes a hairpin type bonding pattern.

The hairpin detector 114 then assess those hairpin structures found by the previous step, comparing them to hairpins of known miRNA genes, using various parameters such as length, free-energy, amount and type of mismatches, etc. Only hairpins that bear statistically significant resemblance of the population of hairpins of known miRNAs, according to the abovementioned parameters are accepted.

Lastly, the hairpin detector 114 attempts to select those hairpin structures which are as stable as the hairpins of know miRNA genes. This may be achieved in various manners. A preferred embodiment of the present invention utilizes the following methodology comprising three steps:

First, the hairpin detector 114 attempts to group potential hairpins into ‘families’ of closely related hairpins. As is known in the art, a free-energy calculation algorithm, typically provides multiple ‘versions’ each describing a different possible 2D folding pattern for the given genomic sequence, and the free energy of such possible folding. The hairpin detector 114 therefore preferably assesses all hairpins found on all ‘versions’, grouping hairpins which appear in different versions, but which share near identical locations into a common ‘family’ of hairpins. For example, all hairpins in different versions, the center of which is within 7 nucleotides of each other may preferably be grouped to a single ‘family’.

Next, hairpin ‘families’ are assessed, in order to select only those families which represent hairpins that are as stable as those of known miRNA hairpins. For example, preferably only families which are represented in at least 65% of the free-energy calculation 2D folding versions, are considered stable.

Finally, an attempt is made to select the most suitable hairpin from each selected family. For example, preferably the hairpin which appears in more versions than other hairpins, and in versions the free-energy of which is lower, may be selected.

Reference is now made to FIG. 6A which is a simplified block diagram of a preferred implementation of the dicer-cut location detector 116 described hereinabove with reference to FIG. 2.

The goal of the dicer-cut location detector 116 is to detect the location in which DICER COMPLEX of FIG. 1, comprising the enzyme Dicer, would ‘dice’ the given hairpin sequence, similar to VGAM FOLDED PRECURSOR RNA, yielding VGAM RNA both of FIG. 1.

The dicer-cut location detector 116 of FIG. 2 therefore receives as input a plurality of hairpins on genomic sequences 138 of FIG. 5A, which were calculated by the previous step, and after a phase of dicer-cut location detector training & validation 126 of FIG. 3, is operative to detect a respective plurality of dicer-cut sequences from hairpins 140, one for each hairpin.

In a preferred embodiment of the present invention, the dicer-cut location detector 116 preferably uses a combination of neural networks, Bayesian networks, Markovian modeling, and Support Vector Machines (SVMs) trained on the known dicer-cut locations of known miRNA genes, in order to detect dicer-cut locations. Dicer-cut location detector training & validation 126, which is further described hereinbelow with reference to FIG. 6B.

Reference is now made to FIG. 6 B which is a simplified flowchart illustrating a preferred implementation of dicer-cut location detector training & validation 126 of FIG. 3. Dicer-cut location detector 116 first preprocesses known miRNA hairpins and their respective dicer-cut locations, so as to be able to properly analyze them and train the detection system accordingly:

The folding pattern is calculated for each known miRNA, preferably based on free-energy calculation, and the size of the hairpin, the size of the loop at the center of the hairpin, and ‘bulges’ (i.e. mismatched base-pairs) in the folded hairpin are noted.

The dicer-cut location, which is known for known miRNA genes, is noted relative to the above, as well as to the nucleotides in each location along the hairpin. Frequency of identity of nucleotides, and nucleotide-pairing, relative to their location in the hairpin, and relative to the known dicer-cut location in the known miRNA genes is analyzed and modeled.

Different techniques are well known in the art for analysis of existing pattern from a given ‘training set’ of species belonging to a genus, which techniques are then capable, to a certain degree, to detect similar patterns in other species not belonging to the training-set genus. Such techniques include, but are not limited to neural networks, Bayesian networks, Support Vector Machines (SVM), Genetic Algorithms, Markovian modeling, and others, as is well known in the art.

Using such techniques, preferably a combination of several of the above techniques, the known hairpins are represented as a several different networks (such as neural, Bayesian, or SVM) input and output layers. Both nucleotide, and ‘bulge’ (i.e. nucleotide pairing or mismatch) are represented for each position in the hairpin, at the input layer, and a corresponding true/false flag at each position, indicating whether it was diced by dicer at the output layer. Multiple networks are preferably used concurrently, and the results therefrom are integrated and further optimized. Markovian modeling may also be used to validate the results and enhance their accuracy. Finally, the bioinformatic detection of dicer-cut location of a sample novel is confirmed by wet-lab experimentation.

Reference is now made to FIG. 7A which is a simplified block diagram of a preferred implementation of the target-gene binding-site detector 118 described hereinabove with reference to FIG. 2. The goal of the target-gene binding-site detector 118 is to detect a BINDING SITE of FIG. 1, located in an untranslated region of the RNA of a known gene, the nucleotide sequence of which BINDING SITE is at least partially complementary to that of a VGAM RNA of FIG. 1, thereby determining that the abovementioned known gene is a target gene of VGAM of FIG. 1.

The target-gene binding-site detector 118 of FIG. 2 therefore receives as input a plurality of dicer-cut sequences from hairpins 140 of FIG. 6A which were calculated by the previous step, and a plurality of potential target gene sequences 142 which derive sequence DNA data 104 of FIG. 2, and after a phase of target-gene binding-site detector training & validation 128 of FIG. 3, is operative to detect target-genes having binding site/s 144 the nucleotide sequence of which is at least partially complementary to that of each of the plurality of dicer-cut sequences from hairpins 140. Preferred operation of the target-gene binding-site detector is further described hereinbelow with reference to FIG. 7B.

Reference is now made to FIG. 7B which is a simplified flowchart illustrating a preferred operation of the target-gene binding-site detector 118 of FIG. 2. In a preferred embodiment of the present invention, the target-gene binding-site detector 118 first performs a BLAST comparison of the nucleotide sequence of each of the plurality of dicer-cut sequences from hairpins 140, to the potential target gene sequences 142, in order to find crude potential matches. Blast results are then filtered to results which are similar to those of known binding sites (e.g. binding sites of miRNA genes Lin-4 and Let-7 to target genes Lin-14, Lin-41, Lin 28 etc.). Next the binding site is expanded, checking if nucleotide sequenced immediately adjacent to the binding site found by BLAST, may improve the match. Suitable binding sites, then are computed for free-energy and spatial structure. The results are analyzed, selecting only those binding sites, which have free-energy and spatial structure similar to that of known binding sites.

Reference is now made to FIG. 8 which is a simplified flowchart illustrating a preferred operation of the function & utility analyzer 120 described hereinabove with reference to FIG. 2. The goal of the function & utility analyzer 120 is to determine if a potential target gene is in fact a valid clinically useful target gene. Since a potential novel VGAM gene binding a binding site in the UTR of a target gene is understood to inhibit expression of that target gene, and if that target gene is shown to have a valid clinical utility, then in such a case it follows that the potential novel gene itself also has a valid useful function—which is the opposite of that of the target gene.

The function & utility analyzer 120 preferably receives as input a plurality of potential novel target genes having binding-site/s 144, generated by the target-gene binding-site detector 118, both of FIG. 7A. Each potential gene, is evaluated as follows:

First the system first checks to see if the function of the potential target gene is scientifically well established. Preferably, this can be achieved bioinformatically by searching various published data sources presenting information on known function of proteins. Many such data sources exist and are published as is well known in the art.

Next, for those target genes the function of which is scientifically known and is well documented, the system then checks if scientific research data exists which links them to known diseases. For example, a preferred embodiment of the present invention utilizes the OMIM™ database published by NCBI, which summarizes research publications relating to genes which have been shown to be associated with diseases.

Finally, the specific possible utility of the target gene is evaluated. While this process too may be facilitated by bioinformatic means, it might require human evaluation of published scientific research regarding the target gene, in order to determine the utility of the target gene to the diagnosis and or treatment of specific disease. Only potential novel genes, the target-genes of which have passed all three examinations, are accepted as novel genes.

Reference is now made to FIG. 9, which is a simplified diagram describing a novel bioinformatically detected group of regulatory genes, referred to here as Genomic Record (GR) genes, that encode an ‘operon-like’ cluster of novel miRNA-like genes, each modulating expression of a plurality of host target, the function and utility of which target genes is known.

GR GENE (Genomic Record Gene) is gene of a novel, bioinformatically detected group of regulatory, non protein coding, RNA genes. The method by which GR is detected is described hereinabove with reference to FIGS. 6-15.

GR GENE encodes an RNA molecule, typically several hundred nucleotides long, designated GR PRECURSOR RNA.

GR PRECURSOR RNA folds spatially, as illustrated by GR FOLDED PRECURSOR RNA, into a plurality of what is known in the art as ‘hair-pin’ structures. The nucleotide sequence of GR PRECURSOR RNA comprises a plurality of segments, the first half of each such segment having a nucleotide sequence which is at least a partial inversed-reversed sequence of the second half thereof, thereby causing formation of a plurality of ‘hairpin’ structures, as is well known in the art.

GR FOLDED PRECURSOR RNA is naturally processed by cellular enzymatic activity, into 3 separate hairpin shaped RNA segments, each corresponding to VGAM PRECURSOR RNA of FIG. 1, designated VGAM1 PRECURSOR, VGAM2 PRECURSOR and VGAM3 PRECURSOR respectively.

The above mentioned VGAM precursors, are diced by Dicer of FIG. 1, yielding short RNA segments of about 22 nucleotides in length, each corresponding to VGAM RNA of FIG. 1, designated VGAM1, VGAM2 and VGAM3 respectively.

VGAM1, VGAM2 and VGAM3 each bind complementarily to binding sites located in untranslated regions of respective host target, designated VGAM1-TARGET RNA, VGAM2-TARGET RNA and VGAM3-TARGET RNA respectively. This binding inhibits translation of the respective target proteins designated VGAM1-TARGET PROTEIN, VGAM2-TARGET PROTEIN and VGAM3-TARGET PROTEIN respectively.

The structure of VGAM genes comprised in a GR GENE, and their mode of modulation of expression of their respective target genes is described hereinabove with reference to FIG. 1. The bioinformatic approach to detection of VGAM genes comprised in a GR GENE is described hereinabove with reference to FIGS. 9 through 14.

The present invention discloses 221 novel viral genes of the GR group of genes, which have been detected bioinformatically, as described hereinbelow with reference to FIGS. 3088 through 3308. Laboratory confirmation of 3 genes of the GR group of genes is described hereinbelow with reference to FIGS. 9A through 14.

In summary, the current invention discloses a very large number of novel viral GR genes, each of which encodes a plurality of VGAM genes, which in turn may modulate expression of a plurality of host target proteins.

Reference is now made to FIG. 10 which is a block diagram illustrating different utilities of genes of the novel group of genes of the present invention referred to here as VGAM genes and GR genes.

The present invention discloses a first plurality of novel genes referred to here as VGAM genes, and a second plurality of operon-like genes referred to here as GR genes, each of the GR genes encoding a plurality of VGAM genes. The present invention further discloses a very large number of known target-genes, which are bound by, and the expression of which is modulated by each of the novel genes of the present invention. Published scientific data referenced by the present invention provides specific, substantial, and credible evidence that the abovementioned target genes modulated by novel genes of the present invention, are associated with various diseases. Specific novel genes of the present invention, target genes thereof and diseases associated therewith, are described hereinbelow with reference to FIGS. 15 through 3829. It is therefore appreciated that a function of VGAM genes and GR genes of the present invention is modulation of expression of target genes related to known diseases, and that therefore utilities of novel genes of the present invention include diagnosis and treatment of the abovementioned diseases. FIG. 10 describes various types of diagnostic and therapeutic utilities of novel genes of the present invention.

A utility of novel genes of the present invention is detection of VGAM genes and of GR genes. It is appreciated that since VGAM genes and GR genes modulate expression of disease related target genes, that detection of expression of VGAM genes in clinical scenarios associated with said diseases is a specific, substantial and credible utility. Diagnosis of novel genes of the present invention may preferably be implemented by RNA expression detection techniques, including but not limited to biochips, as is well known in the art. Diagnosis of expression of genes of the present invention may be useful for research purposes, in order to further understand the connection between the novel genes of the present invention and the abovementioned related diseases, for disease diagnosis and prevention purposes, and for monitoring disease progress.

Another utility of novel genes of the present invention is anti-VGAM gene therapy, a mode of therapy which allows up regulation of a disease related target-gene of a novel VGAM gene of the present invention, by lowering levels of the novel VGAM gene which naturally inhibits expression of that target gene. This mode of therapy is particularly useful with respect to target genes which have been shown to be under-expressed in association with a specific disease. Anti-VGAM gene therapy is further discussed hereinbelow with reference to FIGS. 11A and 11B.

A further utility of novel genes of the present invention is VGAM replacement therapy, a mode of therapy which achieves down regulation of a disease related target-gene of a novel VGAM gene of the present invention, by raising levels of the VGAM gene which naturally inhibits expression of that target gene. This mode of therapy is particularly useful with respect to target genes which have been shown to be over-expressed in association with a specific disease. VGAM replacement therapy involves introduction of supplementary VGAM gene products into a cell, or stimulation of a cell to produce excess VGAM gene products. VGAM replacement therapy may preferably be achieved by transfecting cells with an artificial DNA molecule encoding a VGAM gene, which causes the cells to produce the VGAM gene product, as is well known in the art.

Yet a further utility of novel genes of the present invention is modified VGAM therapy. Disease conditions are likely to exist, in which a mutation in a binding site of a VGAM gene prevents natural VGAM gene to effectively bind inhibit a disease related target-gene, causing up regulation of that target gene, and thereby contributing to the disease pathology. In such conditions, a modified VGAM gene is designed which effectively binds the mutated VGAM binding site, i.e. is an effective anti-sense of the mutated VGAM binding site, and is introduced in disease effected cells. Modified VGAM therapy is preferably achieved by transfecting cells with an artificial DNA molecule encoding the modified VGAM gene, which causes the cells to produce the modified VGAM gene product, as is well known in the art.

An additional utility of novel genes of the present invention is induced cellular differentiation therapy. As aspect of the present invention is finding genes which determine cellular differentiation, as described hereinabove with reference to FIG. 11. Induced cellular differentiation therapy comprises transfection of cell with such VGAM genes thereby determining their differentiation as desired. It is appreciated that this approach may be widely applicable, inter alia as a means for auto transplantation—harvesting cells of one cell-type from a patient, modifying their differentiation as desired, and then transplanting them back into the patient. It is further appreciated that this approach may also be utilized to modify cell differentiation in vivo, by transfecting cells in a genetically diseased tissue with a cell-differentiation determining VGAM gene, thus stimulating these cells to differentiate appropriately.

Reference is now made to FIGS. 11A and 11B, simplified diagrams which when taken together illustrate anti-VGAM gene therapy mentioned hereinabove with reference to FIG. 10. A utility of novel genes of the present invention is anti-VGAM gene therapy, a mode of therapy which allows up regulation of a disease related target-gene of a novel VGAM gene of the present invention, by lowering levels of the novel VGAM gene which naturally inhibits expression of that target gene. FIG. 11A shows a normal VGAM gene, inhibiting translation of a target gene of VGAM gene, by binding to a BINDING SITE found in an untranslated region of TARGET RNA, as described hereinabove with reference to FIG. 1.

FIG. 11B shows an example of anti-VGAM gene therapy. ANTI-VGAM RNA is short artificial RNA molecule the sequence of which is an anti-sense of VGAM RNA. Anti-VGAM treatment comprises transfecting diseased cells with ANTI-VGAM RNA, or with a DNA encoding thereof. The ANTI-VGAM RNA binds the natural VGAM RNA, thereby preventing binding of natural VGAM RNA to its BINDING SITE. This prevents natural translation inhibition of TARGET RNA by VGAM RNA, thereby up regulating expression of TARGET PROTEIN.

It is appreciated that anti-VGAM gene therapy is particularly useful with respect to target genes which have been shown to be under-expressed in association with a specific disease.

Reference is now made to FIG. 12A which is an annotated sequence of an EST comprising a novel gene detected by the gene detection system of the present invention. FIG. 12A shows the nucleotide sequence of a known human non-protein coding EST (Expressed Sequence Tag), identified as EST72223. It is appreciated that the sequence of this EST comprises sequences of one known miRNA gene, identified as MIR98, and of one novel GAM gene, referred to here as GAM24, detected by the bioinformatic gene detection system of the present invention, described hereinabove with reference to FIG. 2.

Reference is now made to FIGS. 12B and 12C that are pictures of laboratory results, which when taken together demonstrate laboratory confirmation of expression of the bioinformatically detected novel gene of FIG. 12A. Reference is now made to FIG. 12B which is a Northern blot analysis of MIR-98 and EST72223 transcripts. MIR-98 and EST72223 were reacted with MIR-98 and GAM24 probes as indicated in the figure. It is appreciated that the probes of both MIR-98 and GAM24 reacted with EST72223, indicating that EST72223 contains the sequences of MIR-98 and of GAM24. It is further appreciated that the probe of GAM24 does not cross-react with MIR-98.

Reference is now made to FIG. 12C. A Northern blot analysis of EST72223 and MIR-98 transfections were performed, subsequently marking RNA by the MIR-98 and GAM24 probes. Left, Northern reacted with MIR-98, Right, Northern reacted with GAM24. The molecular Sizes of EST72223, MIR-98 and GAM24 are indicated by arrows. Hela are control cells that have not been introduced to exogenous RNA. EST and MIR-98 Transfections are RNA obtained from Hela transfected with EST72223 and MIR-98, respectively. MIR-98 and EST are the transcripts used for the transfection experiment. The results indicate that EST72223, when transfected into Hela cells, is cut yielding known miRNA gene MIR-98 and novel miRNA gene GAM24.

Reference is now made to FIG. 12D, which is a Northern blot of a lisate experiment with MIR-98 and GAM24. Northern blot analysis of hairpins in EST72223. Left, Northern reacted with predicted Mir-98 hairpin probe, Right, Northern reacted with predicted GAM24 hairpin probe. The molecular size of EST Is indicated by arrow. The molecular sizes of Mir-98 and GAM24 are 80 nt and 100 nt, respectively as indicated by arrows. The 22 nt molecular marker is indicated by arrow. 1-Hela lysate; 2-EST incubated 4 h with Hela lysate; 3-EST without lysate; 4-Mir transcript incubated 4 h with Hela lysate; 5-Mir transcript incubated overnight with Hela lysate; 6-Mir transcript without lysate; 7-RNA extracted from Hela cells following transfection with Mir transcript.

Technical methods used in experiments, the results of which are depicted in FIGS. 12B, 12C and 12D are as follows:

Transcript Preparations:

Digoxigenin (DIG) labeled transcripts were prepared from EST72223 (TIGER), MIR98 and predicted precursor hairpins by using a DIG RNA labeling kit (Roche Molecular Biochemicals) according to the manufacture's protocol. Briefly, PCR products with T7 promoter at the 5′ end or T3 promoter at the 3′ end were prepared from each DNA in order to use it as a template to prepare sense and antisense transcripts, respectively.

-   -   MIR-98 was amplified using EST72223 as a templet with T7miR98         forward primer: 5-′TAATACGACTCACTATAGGGTGAGGTAGTAAGTTGTATTGTT-3′         and T3miR98 revse primer:         5′-AATTAACCCTCACTAAAGGGAAAGTAGTAAGTTGTATAGTT-3′ EST72223 was         amplified with T7-EST 72223 forward primer:         5′-TAATACGACTCACTATAGGCCCTTATTAGAGGATTCTGCT-3′ and T3-EST72223         reverse primer: 5′-AATTAACCCTCACTAAAGGTTTTTTTTTCCTGAGACAGAGT-3′         Bet-4 was amplified using EST72223 as a templet with Bet-4         forward primer: 5′-GAGGCAGGAGAATTGCTTGA-3′ and T3-EST72223         reverse primer: 5′-AATTAACCCTCACTAAAGGCCTGAGACAGAGTCTTGCTC-3′

The PCR products were cleaned and used for DIG-labeled or unlabeled transcription reactions with the appropriate polymerase. For transfection experiments, CAP reaction was performed by using a mMassage mMachine kit (Ambion).

Transfection Procedure:

Transfection of Hela cells was performed by using TransMessenger reagent (Qiagen) according to the manufacture's protocol. Briefly, Hela cells were seeded to 1-2×10̂6 cells per plate a day before transfection. Two μg RNA transcripts were mixed with 8 μl Enhancer in a final volume of 100 μl, mixed and incubated at room temperature for 5 min. 16 μl TransMessenger reagent was added to the RNA-Enhancer, mixed and incubated for additional 10 min. Cell plates were washed with sterile PBS twice and then incubated with the transfection mix diluted with 2.5 ml DMEM medium without serum. Cells were incubated with transfection mix for three hours under their normal growth condition (370 C and 5% CO2) before the transfection mix was removed and a fresh DMEM medium containing serum was added to the cells. Cells were left to grow 48 hours before harvesting.

Target RNA Cleavage Assay:

Cap-labeled target RNAs were generated using mMessage mMachine™ (Ambion). Caped RNA transcripts were preincubated at 30° C. for 15 min in supplemented Hela S100 obtained from Computer Cell Culture, Mos, Belgium. After addition of all components, final concentrations were 100 mM target RNA, 1 m M ATP, 0.2 mM GTP, 10 U/ml RNasin, 30 μg/ml creatine kinase, 25 mM creatine phosphate, and 50% S100 extract. Incubation was continued for 4 hours to overnight. Cleavage reaction was stopped by the addition of 8 volumes of proteinase K buffer (200 Mm Tris-Hcl, pH 7.5, 25 m M EDTA, 300 mM NaCl, and 2% SDS). Proteinase K, dissolved in 50 mM Tris-HCl, pH 8, 5 m M CaCl2, and 50% glycerol, was added to a final concentration of 0.6 mg/ml. Sample were subjected to phenol/chlorophorm extraction and kept frozen until analyzed by urea-TBE PAGE.

Northern Analysis:

RNAs were extracted from cells by using Tri-reagent according to the manufacture's protocol. The RNAs were dissolved in water and heated to 650 C to disrupt any association of the 25 nt RNA with larger RNA molecules. RNA were placed on ice and incubated for 30 min with PEG (MW=8000) in a final concentration of 5% and NaCl in a final concentration of 0.5M to precipitate high molecular weight nucleic acid. The RNAs were centrifuged at 10,000×g for 10 min to pellet the high molecular weight nucleic acid. The supernatant containing the low molecular weight RNAs was collected and three volumes of ethanol was added. The RNAs were placed at −200 C for at least two hours and then centrifuged at 10,000×g for 10 min. The pellets were dissolved in Urea-TBE buffer (1Xtbe, 7M urea) for further analysis by a Northern blot.

RNA samples were boiled for 5 min before loading on 15%-8% polyacrylamide (19:1) gels containing 7M urea and 1×TBE. Gels were run in 1×TBE at a constant voltage of 300V and then transferred into a nylon membrane. The membrane was exposed to 3 min ultraviolet light to cross link the RNAs to the membrane. Hybridization was performed overnight with DIG-labeled probes at 420 C. Membranes were washed twice with SSCx2 and 0.2% SDS for 10 min. at 420 C and then washed twice with SSCx0.5 for 5 min at room temperature. The membrane was then developed by using a DIG luminescent detection kit (Roche) using anti DIG and CSPD reaction, according to the manufacture's protocol.

It is appreciated that the data presented in FIGS. 12A, 12B, 12C and 12D, when taken together validate the function of the bioinformatic gene detection engine 100 of FIG. 2. FIG. 12A shows a novel GAM gene bioinformatically detected by the bioinformatic gene detection engine 100, and FIGS. 12B, 12C and 12D show laboratory confirmation of the expression of this novel gene. This is in accord with the engine training and validation methodology described hereinabove with reference to FIG. 3.

Reference is now made to FIG. 13A which is an annotated sequence of an EST comprising a novel gene detected by the gene detection system of the present invention. FIG. 13A shows the nucleotide sequence of a known human non-protein coding EST (Expressed Sequence Tag), identified as EST 7929020. It is appreciated that the sequence of this EST comprises sequences of two novel GAM genes, referred to here as GAM23 and GAM25, detected by the bioinformatic gene detection system of the present invention, described hereinabove with reference to FIG. 2.

Reference is now made to FIG. 13B which presents pictures of laboratory results, that demonstrate laboratory confirmation of expression of the bioinformatically detected novel gene of FIG. 13A. Northern blot analysis of hairpins in EST7929020. Left, Northern reacted with predicted GAM25 hairpin probe, Right, Northern reacted with predicted GAM23 hairpin probe. The molecular size of EST is indicated by arrow. The molecular sizes of GAM23 and GAM25 are 60 nt, as indicated by arrow. The 22 nt molecular marker is indicated by arrow. 1-Hela lysate; 2-EST incubated 4 h with Hela lysate; 3-EST incubated overnight with Hela lysate; 4-EST without lysate; 5-GAM transcript; 6-GAM 22 nt marker; 7-GAM PCR probe; 8-RNA from control Hela cells; 9-RNA extracted from Hela cells following transfection with EST.

Reference is now made to FIG. 13C which is a picture of a Northern blot confirming Endogenous expression of bioinformatically detected gene GAM25 of FIG. 13A from in Hela cells. Northern was reacted with a predicted GAM25 hairpin probe. The molecular size of EST7929020 is indicated. The molecular sizes of GAM25 is 58 nt, as indicated. A 19 nt DNA oligo molecular marker is indicated. Endogenous expression of GAM25 in Hela total RNA fraction and in S-100 fraction is indicated by arrows. 1-GAM25 transcript; 2-GAM25 DNA oligo marker; 3-RNA from control Hela cells; 4-RNA extracted from Hela cells following transfection with EST; 5-RNA extracted from S-100 Hela lysate.

Reference is now made to FIG. 14A which is an annotated sequence of an EST comprising a novel gene detected by the gene detection system of the present invention. FIG. 14A shows the nucleotide sequence of a known human non-protein coding EST (Expressed Sequence Tag), identified as EST 1388749. It is appreciated that the sequence of this EST comprises sequence of a novel GAM gene, referred to here as GAM26, detected by the bioinformatic gene detection system of the present invention, described hereinabove with reference to FIG. 2.

Reference is now made to FIG. 14B which is a picture of Northern blot analysis, confirming expression of novel bioinformatically detected gene GAM26, and natural processing thereof from EST1388749. Northern reacted with predicted GAM26 hairpin probe. The molecular size of EST is indicated by arrow. The molecular sizes of GAM26 is 130 nt, as indicated by arrow. The 22 nt molecular marker is indicated by arrow. 1-Hela lysate; 2-EST incubated 4 h with Hela lysate; 3-EST incubated overnight with Hela lysate; 4-EST without lysate; 5-GAM transcript; 6-GAM 22 nt marker; 7-GAM PCR probe.

Reference is now made to FIG. 15A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 15 (VGAM15) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM15 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM15 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM15 GENE is a viral gene contained in the genome of Melanoplus sanguinipes entomopoxvirus. VGAM15-HOST TARGET GENE is a human gene contained in the human genome.

VGAM15 GENE encodes a VGAM15 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM15, VGAM15 PRECURSOR RNA, does not encoded a protein.

VGAM15 PRECURSOR RNA folds onto itself, forming VGAM15 FOLDED PRECURSOR RNA. As FIG. 15 illustrates, VGAM15 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM15 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM15 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM15-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM15-HOST-TARGET RNA. VGAM15-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM15 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM15-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM15 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 15A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM15 RNA to HOST BINDING SITE inhibits translation of VGAM15-HOST-TARGET RNA into VGAM15-HOST-TARGET PROTEIN. VGAM15-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM15-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM15. The mRNA of each of this plurality of host target genes of VGAM15 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM15 RNA, and which when bound by VGAM15 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM15. The plurality of host target genes of VGAM15 and their respective host binding sites, are described hereinbelow with reference to FIG. 15D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 15A with specific reference to translational inhibition exerted by VGAM15 on one or more host target genes of VGAM15, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM15 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM15 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

Reference is now made to FIG. 15B which shows the nucleotide sequence of VGAM15 PRECURSOR RNA of FIG. 15A, designated SEQ ID:1, and a probable nucleotide sequence of VGAM15 RNA of FIG. 15A, designated SEQ ID:2. The nucleotide sequence of SEQ ID:2, which is highly likely (over 35%) to be identical or highly similar to that of VGAM15, is marked by an underline within the sequence of VGAM15 PRECURSOR RNA.

Reference is now made to FIG. 15C, which shows the secondary folding of VGAM15 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM15 FOLDED PRECURSOR RNA, both of FIG. 15A. A probable (>35%) nucleotide sequence of VGAM15 RNA, designated SEQ ID:2 of FIG. 15B, is marked by an underline on VGAM15 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 15D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM15, each binding site corresponding to HOST BINDING SITE of FIG. 15A, and their complementarity to SEQ ID:2, which is highly likely (>35%) to be identical or highly similar to the nucleotide sequence of VGAM15 RNA of FIG. 15A.

As mentioned hereinabove with reference to FIG. 15A a function of VGAM15 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM15 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus. It is appreciated that specific functions, and accordingly utilities, of VGAM15 correlate with, and may be deduced from, the identity of the host target genes which VGAM15 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to KCNK4 BINDING SITE. potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4) is a host target gene of VGAM15, corresponding to VGAM15-HOST-TARGET GENE of FIG. 15A. KCNK4 BINDING SITE is a host binding site found in the 3′ untranslated region of KCNK4, corresponding to HOST BINDING SITE of FIG. 15A. FIG. 15D illustrates the complementarity of the nucleotide sequence of KCNK4 BINDING SITE, designated SEQ ID:3, to the nucleotide sequence of VGAM15 RNA of FIG. 15A, designated SEQ ID:2.

A function of VGAM15 is therefore inhibition of potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4), a host gene which encodes a Protein that is a voltage insensitive, instantaneous, outwardly rectifying potassium channel, as part of a novel viral mechanism used by Melanoplus sanguinipes entomopoxvirus for attacking a host. Accordingly, utilities of VGAM15 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

The function of KCNK4 has been established by previous studies. Potassium channels are functionally important to a large number of cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. Mammalian potassium channels with 4 transmembrane segments and 2 pore (P2) domains in tandem form a distinct class of K+ channels. By database searching with sequences of known P2 domain K+ channels, Lesage et al. (2000) identified human sequences showing homology to the mouse P2 domain K+ channel Traak. Using degenerate PCR with primers based on these genomic sequences, Lesage et al. (2000) isolated a human P2 K+ channel cDNA, designated TRAAK or KCNK4, from a brain cDNA library. The deduced 393-amino acid protein shares 82% sequence identity with the mouse homolog. By RT-PCR, Lesage et al. (2000) demonstrated high expression of human KCNK4 in brain and placenta, with weak expression in testis, small intestine, prostate, and kidney. Mouse Kcnk4 is not expressed in placenta but, like the human transcript, is highly expressed only in neuronal tissues. Electrophysiologic studies in COS cells expressing KCNK4 indicated that human KCNK4 shares the same biophysical and pharmacologic properties as mouse TRAAK. KCNK4 currents are K+ selective, instantaneous, noninactivating, and outwardly rectifying. They are not sensitive to classic K+ channel blockers such as quinidine, TEA, and barium, but are potentiated by polyunsaturated fatty acids such as arachidonic acid. Lesage et al. (2000) determined that the KCNK4 gene contains 6 exons, with an intron in the first pore domain. The position of this intron is conserved in many P2 domain K+ channels, including some in C. elegans. By radiation hybrid analysis, Lesage et al. (2000) mapped the KCNK4 gene to chromosome 11q13, close to another P2 domain K+ channel, KCNK7 (603940).

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Esage, F.; Maingret, F.; Lazdunski, M.: Cloning and expression of     human TRAAK, a polyunsaturated fatty acids-activated and     mechano-sensitive K+ channel. FEBS Lett. 471: 137-140, 2000.

Further studies establishing the function and utilities of KCNK4 are found in John Hopkins OMIM database record ID 605720, and in references numbered 1 listed hereinbelow.

Reference is now made to KCNK4 BINDING SITE. potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4) is a host target gene of VGAM15, corresponding to VGAM15-HOST-TARGET GENE of FIG. 15A. KCNK4 BINDING SITE is a host binding site found in the 3′ untranslated region of KCNK4, corresponding to HOST BINDING SITE of FIG. 15A. FIG. 15D illustrates the complementarity of the nucleotide sequence of KCNK4 BINDING SITE, designated SEQ ID:3, to the nucleotide sequence of VGAM15 RNA of FIG. 15A, designated SEQ ID:2.

A function of VGAM15 is therefore inhibition of potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4), a host gene which encodes a Protein that is a voltage insensitive, instantaneous, outwardly rectifying potassium channel, as part of a novel viral mechanism used by Melanoplus sanguinipes entomopoxvirus for attacking a host. Accordingly, utilities of VGAM15 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

The function of KCNK4 has been established by previous studies. Potassium channels are functionally important to a large number of cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. Mammalian potassium channels with 4 transmembrane segments and 2 pore (P2) domains in tandem form a distinct class of K+ channels. By database searching with sequences of known P2 domain K+ channels, Lesage et al. (2000) identified human sequences showing homology to the mouse P2 domain K+ channel Traak. Using degenerate PCR with primers based on these genomic sequences, Lesage et al. (2000) isolated a human P2 K+ channel cDNA, designated TRAAK or KCNK4, from a brain cDNA library. The deduced 393-amino acid protein shares 82% sequence identity with the mouse homolog. By RT-PCR, Lesage et al. (2000) demonstrated high expression of human KCNK4 in brain and placenta, with weak expression in testis, small intestine, prostate, and kidney. Mouse Kcnk4 is not expressed in placenta but, like the human transcript, is highly expressed only in neuronal tissues. Electrophysiologic studies in COS cells expressing KCNK4 indicated that human KCNK4 shares the same biophysical and pharmacologic properties as mouse TRAAK. KCNK4 currents are K+ selective, instantaneous, noninactivating, and outwardly rectifying. They are not sensitive to classic K+ channel blockers such as quinidine, TEA, and barium, but are potentiated by polyunsaturated fatty acids such as arachidonic acid. Lesage et al. (2000) determined that the KCNK4 gene contains 6 exons, with an intron in the first pore domain. The position of this intron is conserved in many P2 domain K+ channels, including some in C. elegans. By radiation hybrid analysis, Lesage et al. (2000) mapped the KCNK4 gene to chromosome 11q13, close to another P2 domain K+ channel, KCNK7 (603940).

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Esage, F.; Maingret, F.; Lazdunski, M.: Cloning and expression of     human TRAAK, a polyunsaturated fatty acids-activated and     mechano-sensitive K+ channel. FEBS Lett. 471: 137-140, 2000.

Further studies establishing the function and utilities of KCNK4 are found in John Hopkins OMIM database record ID 605720, and in references numbered 1 listed hereinbelow.

Reference is now made to KCNK4 BINDING SITE. potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4) is a host target gene of VGAM15, corresponding to VGAM15-HOST-TARGET GENE of FIG. 15A. KCNK4 BINDING SITE is a host binding site found in the 3′ untranslated region of KCNK4, corresponding to HOST BINDING SITE of FIG. 15A. FIG. 15D illustrates the complementarity of the nucleotide sequence of KCNK4 BINDING SITE, designated SEQ ID:3, to the nucleotide sequence of VGAM15 RNA of FIG. 15A, designated SEQ ID:2.

A function of VGAM15 is therefore inhibition of potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4), a host gene which encodes a Protein that is a voltage insensitive, instantaneous, outwardly rectifying potassium channel, as part of a novel viral mechanism used by Melanoplus sanguinipes entomopoxvirus for attacking a host. Accordingly, utilities of VGAM15 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

The function of KCNK4 has been established by previous studies. Potassium channels are functionally important to a large number of cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. Mammalian potassium channels with 4 transmembrane segments and 2 pore (P2) domains in tandem form a distinct class of K+ channels. By database searching with sequences of known P2 domain K+ channels, Lesage et al. (2000) identified human sequences showing homology to the mouse P2 domain K+ channel Traak. Using degenerate PCR with primers based on these genomic sequences, Lesage et al. (2000) isolated a human P2 K+ channel cDNA, designated TRAAK or KCNK4, from a brain cDNA library. The deduced 393-amino acid protein shares 82% sequence identity with the mouse homolog. By RT-PCR, Lesage et al. (2000) demonstrated high expression of human KCNK4 in brain and placenta, with weak expression in testis, small intestine, prostate, and kidney. Mouse Kcnk4 is not expressed in placenta but, like the human transcript, is highly expressed only in neuronal tissues. Electrophysiologic studies in COS cells expressing KCNK4 indicated that human KCNK4 shares the same biophysical and pharmacologic properties as mouse TRAAK. KCNK4 currents are K+ selective, instantaneous, noninactivating, and outwardly rectifying. They are not sensitive to classic K+ channel blockers such as quinidine, TEA, and barium, but are potentiated by polyunsaturated fatty acids such as arachidonic acid. Lesage et al. (2000) determined that the KCNK4 gene contains 6 exons, with an intron in the first pore domain. The position of this intron is conserved in many P2 domain K+ channels, including some in C. elegans. By radiation hybrid analysis, Lesage et al. (2000) mapped the KCNK4 gene to chromosome 11q13, close to another P2 domain K+ channel, KCNK7 (603940).

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Esage, F.; Maingret, F.; Lazdunski, M.: Cloning and expression of     human TRAAK, a polyunsaturated fatty acids-activated and     mechano-sensitive K+ channel. FEBS Lett. 471: 137-140, 2000.

Further studies establishing the function and utilities of KCNK4 are found in John Hopkins OMIM database record ID 605720, and in references numbered 1 listed hereinbelow.

Reference is now made to KCNK4 BINDING SITE. potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4) is a host target gene of VGAM15, corresponding to VGAM15-HOST-TARGET GENE of FIG. 15A. KCNK4 BINDING SITE is a host binding site found in the 3′ untranslated region of KCNK4, corresponding to HOST BINDING SITE of FIG. 15A. FIG. 15D illustrates the complementarity of the nucleotide sequence of KCNK4 BINDING SITE, designated SEQ ID:3, to the nucleotide sequence of VGAM15 RNA of FIG. 15A, designated SEQ ID:2.

A function of VGAM15 is therefore inhibition of potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4), a host gene which encodes a Protein that is a voltage insensitive, instantaneous, outwardly rectifying potassium channel, as part of a novel viral mechanism used by Melanoplus sanguinipes entomopoxvirus for attacking a host. Accordingly, utilities of VGAM15 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

The function of KCNK4 has been established by previous studies. Potassium channels are functionally important to a large number of cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. Mammalian potassium channels with 4 transmembrane segments and 2 pore (P2) domains in tandem form a distinct class of K+ channels. By database searching with sequences of known P2 domain K+ channels, Lesage et al. (2000) identified human sequences showing homology to the mouse P2 domain K+ channel Traak. Using degenerate PCR with primers based on these genomic sequences, Lesage et al. (2000) isolated a human P2 K+ channel cDNA, designated TRAAK or KCNK4, from a brain cDNA library. The deduced 393-amino acid protein shares 82% sequence identity with the mouse homolog. By RT-PCR, Lesage et al. (2000) demonstrated high expression of human KCNK4 in brain and placenta, with weak expression in testis, small intestine, prostate, and kidney. Mouse Kcnk4 is not expressed in placenta but, like the human transcript, is highly expressed only in neuronal tissues. Electrophysiologic studies in COS cells expressing KCNK4 indicated that human KCNK4 shares the same biophysical and pharmacologic properties as mouse TRAAK. KCNK4 currents are K+ selective, instantaneous, noninactivating, and outwardly rectifying. They are not sensitive to classic K+ channel blockers such as quinidine, TEA, and barium, but are potentiated by polyunsaturated fatty acids such as arachidonic acid. Lesage et al. (2000) determined that the KCNK4 gene contains 6 exons, with an intron in the first pore domain. The position of this intron is conserved in many P2 domain K+ channels, including some in C. elegans. By radiation hybrid analysis, Lesage et al. (2000) mapped the KCNK4 gene to chromosome 11q13, close to another P2 domain K+ channel, KCNK7 (603940).

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Esage, F.; Maingret, F.; Lazdunski, M.: Cloning and expression of     human TRAAK, a polyunsaturated fatty acids-activated and     mechano-sensitive K+ channel. FEBS Lett. 471: 137-140, 2000.

Further studies establishing the function and utilities of KCNK4 are found in John Hopkins OMIM database record ID 605720, and in references numbered 1 listed hereinbelow.

Reference is now made to KCNK4 BINDING SITE. potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4) is a host target gene of VGAM15, corresponding to VGAM15-HOST-TARGET GENE of FIG. 15A. KCNK4 BINDING SITE is a host binding site found in the 3′ untranslated region of KCNK4, corresponding to HOST BINDING SITE of FIG. 15A. FIG. 15D illustrates the complementarity of the nucleotide sequence of KCNK4 BINDING SITE, designated SEQ ID:3, to the nucleotide sequence of VGAM15 RNA of FIG. 15A, designated SEQ ID:2.

A function of VGAM15 is therefore inhibition of potassium inwardly-rectifying channel, subfamily K, member 4 (KCNK4), a host gene which encodes a Protein that is a voltage insensitive, instantaneous, outwardly rectifying potassium channel, as part of a novel viral mechanism used by Melanoplus sanguinipes entomopoxvirus for attacking a host. Accordingly, utilities of VGAM15 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

The function of KCNK4 has been established by previous studies. Potassium channels are functionally important to a large number of cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. Mammalian potassium channels with 4 transmembrane segments and 2 pore (P2) domains in tandem form a distinct class of K+ channels. By database searching with sequences of known P2 domain K+ channels, Lesage et al. (2000) identified human sequences showing homology to the mouse P2 domain K+ channel Traak. Using degenerate PCR with primers based on these genomic sequences, Lesage et al. (2000) isolated a human P2 K+ channel cDNA, designated TRAAK or KCNK4, from a brain cDNA library. The deduced 393-amino acid protein shares 82% sequence identity with the mouse homolog. By RT-PCR, Lesage et al. (2000) demonstrated high expression of human KCNK4 in brain and placenta, with weak expression in testis, small intestine, prostate, and kidney. Mouse Kcnk4 is not expressed in placenta but, like the human transcript, is highly expressed only in neuronal tissues. Electrophysiologic studies in COS cells expressing KCNK4 indicated that human KCNK4 shares the same biophysical and pharmacologic properties as mouse TRAAK. KCNK4 currents are K+ selective, instantaneous, noninactivating, and outwardly rectifying. They are not sensitive to classic K+ channel blockers such as quinidine, TEA, and barium, but are potentiated by polyunsaturated fatty acids such as arachidonic acid. Lesage et al. (2000) determined that the KCNK4 gene contains 6 exons, with an intron in the first pore domain. The position of this intron is conserved in many P2 domain K+ channels, including some in C. elegans. By radiation hybrid analysis, Lesage et al. (2000) mapped the KCNK4 gene to chromosome 11q13, close to another P2 domain K+ channel, KCNK7 (603940).

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Esage, F.; Maingret, F.; Lazdunski, M.: Cloning and expression of     human TRAAK, a polyunsaturated fatty acids-activated and     mechano-sensitive K+ channel. FEBS Lett. 471: 137-140, 2000.

Further studies establishing the function and utilities of KCNK4 are found in John Hopkins OMIM database record ID 605720, and in references numbered 1 listed hereinbelow.

Reference is now made to FIG. 16A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 16 (VGAM16) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM16 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM16 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM16 GENE is a viral gene contained in the genome of Porcine adenovirus A. VGAM16-HOST TARGET GENE is a human gene contained in the human genome.

VGAM16 GENE encodes a VGAM16 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM16, VGAM16 PRECURSOR RNA, does not encoded a protein.

VGAM16 PRECURSOR RNA folds onto itself, forming VGAM16 FOLDED PRECURSOR RNA. As FIG. 16 illustrates, VGAM16 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM16 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM16 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM16-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM16-HOST-TARGET RNA. VGAM16-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM16 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM16-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM16 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 16A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM16 RNA to HOST BINDING SITE inhibits translation of VGAM16-HOST-TARGET RNA into VGAM16-HOST-TARGET PROTEIN. VGAM16-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM16-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM16. The mRNA of each of this plurality of host target genes of VGAM16 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM16 RNA, and which when bound by VGAM16 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM16. The plurality of host target genes of VGAM16 and their respective host binding sites, are described hereinbelow with reference to FIG. 16D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 16A with specific reference to translational inhibition exerted by VGAM16 on one or more host target genes of VGAM16, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM16 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

Reference is now made to FIG. 16B which shows the nucleotide sequence of VGAM16 PRECURSOR RNA of FIG. 16A, designated SEQ ID:8, and a probable nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9. The nucleotide sequence of SEQ ID: 9, which is highly likely (over 55%) to be identical or highly similar to that of VGAM16, is marked by an underline within the sequence of VGAM16 PRECURSOR RNA.

Reference is now made to FIG. 16C, which shows the secondary folding of VGAM16 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM16 FOLDED PRECURSOR RNA, both of FIG. 16A. A probable (>55%) nucleotide sequence of VGAM16 RNA, designated SEQ ID:9 of FIG. 16B, is marked by an underline on VGAM16 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 16D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM16, each binding site corresponding to HOST BINDING SITE of FIG. 16A, and their complementarity to SEQ ID:9, which is highly likely (>55%) to be identical or highly similar to the nucleotide sequence of VGAM16 RNA of FIG. 16A.

As mentioned hereinabove with reference to FIG. 16A a function of VGAM16 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A. It is appreciated that specific functions, and accordingly utilities, of VGAM16 correlate with, and may be deduced from, the identity of the host target genes which VGAM16 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to DUOX1 BINDING SITE. dual oxidase 1 (DUOX1) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. DUOX1 BINDING SITE is a host binding site found in the 3′ untranslated region of DUOX1, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of DUOX1 BINDING SITE, designated SEQ ID:10, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

A function of VGAM16 is therefore inhibition of dual oxidase 1 (DUOX1), a host gene which encodes a Protein that is a component of the thyroid hydrogen peroxide generating system, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of DUOX1 has been established by previous studies. Using a probe for a leukocyte NADPH oxidase, De Deken et al. (2000) cloned a full-length DUOX1 cDNA from a primary human thyroid cell cDNA library. The deduced 1,551-amino acid protein has a calculated molecular mass of 177 kD. It contains several domains characteristic of flavoproteins including NADPH- and FAD-binding domains, and 4 specific histidines and a conserved arginine predicted to bind a heme prosthetic group. DUOX2 also contains 2 EF-hand motifs, 4 putative N-glycosylation sites, and 7 hydrophobic stretches. It shares 83% and 53% sequence similarity with DUOX2 and gp91-phox (306400), respectively, and significant similarity to other NADPH oxidases. DUOX1 and DUOX2 share 53% and 61% sequence similarity, respectively, with a predicted protein in C. elegans. Northern blot analysis detected expression of a 5.7-kb DUOX1 transcript in cultured human thymocytes. Immunolocalization studies demonstrated that DUOX1 colocalizes with thyroperoxidase at the supranuclear apical pole of all thyroid cells. De Deken et al. (2000) detected upregulated expression of DUOX1 and DUOX2 mRNA in cultured human thymocytes stimulated with cAMP agonists. In a study of thyroid carcinomas, Lacroix et al. (2001) showed that levels of DUOX1 and DUOX2 were maintained in parallel and were more frequently seen in neoplastic tissues expressing other thyroid differentiation markers.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Deken, X.; Wang, D.; Many, M.-C.; Costagliola, S.; Libert, F.;     Vassart, G.; Dumont, J. E.; Miot, F.: Cloning of two human thyroid     cDNAs encoding new members of the NADPH oxidase family. J. Biol.     Chem. 275: 23227-23233, 2000. PubMed ID: 10806195 2. Lacroix, L.;     Nocera, M.; Mian, C.; Caillou, B.; Virion, A.; Dupuy, C.; Filetti,     S.; Bidart, J. M.; Schlumberger, M.: Expression of nicotinamide     adenine dinucleotide phosphate oxidase flavoprotein DUOX genes and     proteins in human papillary and follicular thyroid carcinomas.     Thyroid 11: 1017-1023, 2001.

Further studies establishing the function and utilities of DUOX1 are found in John Hopkins OMIM database record ID 606758, and in references numbered 2-3 listed hereinbelow.

Reference is now made to EPHA8 BINDING SITE. EphA8 (EPHA8) is a host target gene of VGAM16, corresponding to VGAM16-HOST TARGET GENE of FIG. 16A. EPHA8 BINDING SITE is a host binding site found in the 3′ untranslated region of EPHA8, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of EPHA8 BINDING SITE, designated SEQ ID:11, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

Yet another function of VGAM16 is therefore inhibition of EphA8 (EPHA8), a host gene which encodes a receptor that Eph-related receptor tyrosine kinase A8, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EPHA8 has been established by previous studies. See EPH (EPHA1; 179610) for background on Eph receptors and their ligands, the ephrins. Chan and Watt (1991) identified human and rat DNAs encoding 2 novel members of the EPH subclass of putative receptor protein-tyrosine kinases. Rat cDNA clones encoding EEK (EPH- and ELK-related kinase) were isolated from a brain cDNA library probed with DNA encoding the kinase region of the insulin receptor-related receptor (INSRR; 147671). The EEK protein was predicted to contain all the amino acid residues conserved in the catalytic domains of protein-tyrosine kinases and was most similar to 2 putative receptor protein-tyrosine kinases of the EPH subclass, ELK (EPHB1; 600600) and EPH, showing 69 and 57% identity, respectively. Human genomic DNAs, encoding part of EEK as well as another putative protein tyrosine kinase most similar to ELK (90%) and symbolized ERK (EPHB2; 600997) for ELK-related kinase, were isolated and partially characterized. The novel identity of these 2 EPH-family genes was further supported by Southern blot analysis and localization to human chromosome 1. In Northern blot analysis of rat RNA, DNAs encoding rat EEK and human ERK hybridized to transcripts most abundant in brain and lung, respectively. These 2 new members of the EPH subclass of receptor protein-tyrosine kinases, EEK and ERK, may therefore have tissue-specific functions distinct from those of the other EPH family members.

Animal model experiments lend further support to the function of EPHA8. Park et al. (1997) generated mice homozygous for a mutation that disrupts the gene encoding EPHA8, a member of the Eph family of tyrosine proteinase receptors. EphA8−/− mice developed to term, were fertile, and did not display obvious anatomical or physiologic defects.

It is appreciated that the abovementioned animal model for EPHA8 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Han, J.; Watt, V. M.: Eek and erk, new members of the eph subclass     of receptor protein-tyrosine kinases. Oncogene 6: 1057-1061, 1991.     PubMed ID: 1648701 2. Park, S.; Frisen, J.; Barbacid, M.: Aberrant     axonal projections in mice lacking EphA8 (Eek) tyrosine protein     kinase receptors. EMBO J. 16: 3106-3114, 1997.

Further studies establishing the function and utilities of EPHA8 are found in John Hopkins OMIM database record ID 176945, and in references numbered 4-5 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Aashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to UBE2H BINDING SITE. ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H) is a host target gene of VGAM16, corresponding to VGAM16-HOST-TARGET GENE of FIG. 16A. UBE2H BINDING SITE is a host binding site found in the 3′ untranslated region of UBE2H, corresponding to HOST BINDING SITE of FIG. 16A. FIG. 16D illustrates the complementarity of the nucleotide sequence of UBE2H BINDING SITE, designated SEQ ID:12, to the nucleotide sequence of VGAM16 RNA of FIG. 16A, designated SEQ ID:9.

An additional function of VGAM16 is therefore inhibition of ubiquitin-conjugating enzyme E2H (homologous to yeast UBC8) (UBE2H), a host gene which encodes a Enzyme that catalyzes the covalent attachment of ubiquitin to other proteins, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM16 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of UBE2H has been established by previous studies. Ubiquitin-conjugating enzymes catalyze the covalent attachment of ubiquitin to cellular substrates. Kaiser et al. (1994) isolated a novel ubiquitin-conjugating enzyme from human placenta and cloned the corresponding cDNA. DNA sequencing revealed that this gene, symbolized UBCH2 by them, encodes a protein with significant sequence similarity to yeast UBC8. They discovered that yeast UBC8 is interrupted by a single intron bearing an unusual branch point sequence. The authors noted that yeast UBC8 exhibited 54% amino acid sequence identity to human UBCH2. Moreover, full-length yeast and human enzymes expressed from the cDNAs showed similar enzymatic activities in vitro by catalyzing the ubiquitination of histones, suggesting that the 2 enzymes may fulfill similar functions in vivo. By study of hamster/human hybrid cell DNAs, Kaiser et al. (1994) demonstrated that the human UBC8 gene is located on chromosome 7. Hayashida et al. (2000) constructed a 1-Mb physical and transcript map of 7q32 and mapped UBE2H to a region between D7S530 and D7S649.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ayashida, S.; Yamasaki, K.; Asada, Y.; Soeda, E.; Niikawa, N.;     Kishino, T.: Construction of a physical and transcript map flanking     the imprinted MEST/PEG1 region at 7q32. Genomics 66: 221-225, 2000.     PubMed ID: 10860668 2. Kaiser, P.; Seufert, W.; Hofferer, L.;     Kofler, B.; Sachsenmaier, C.; Herzog, H.; Jentsch, S.; Schweiger,     M.; Schneider, R.: Human ubiquitin-conjugating enzyme homologous to     yeast UBC8. J. Biol. Chem. 269: 8797-8802, 1994.

Further studies establishing the function and utilities of UBE2H are found in John Hopkins OMIM database record ID 601082, and in references numbered 6-7 listed hereinbelow.

Reference is now made to FIG. 17A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 17 (VGAM17) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM17 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM17 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM17 GENE is a viral gene contained in the genome of Porcine adenovirus A. VGAM17-HOST TARGET GENE is a human gene contained in the human genome.

VGAM17 GENE encodes a VGAM17 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM17, VGAM17 PRECURSOR RNA, does not encoded a protein.

VGAM17 PRECURSOR RNA folds onto itself, forming VGAM17 FOLDED PRECURSOR RNA. As FIG. 17 illustrates, VGAM17 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM17 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM17 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM17-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM17-HOST-TARGET RNA. VGAM17-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM17 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM17-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM17 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 17A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM17 RNA to HOST BINDING SITE inhibits translation of VGAM17-HOST-TARGET RNA into VGAM17-HOST-TARGET PROTEIN. VGAM17-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM17-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM17. The mRNA of each of this plurality of host target genes of VGAM17 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM17 RNA, and which when bound by VGAM17 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM17. The plurality of host target genes of VGAM17 and their respective host binding sites, are described hereinbelow with reference to FIG. 17D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 17A with specific reference to translational inhibition exerted by VGAM17 on one or more host target genes of VGAM17, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM17 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

Reference is now made to FIG. 17B which shows the nucleotide sequence of VGAM17 PRECURSOR RNA of FIG. 17A, designated SEQ ID:22, and a probable nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23. The nucleotide sequence of SEQ ID:23, which is highly likely (over 28%) to be identical or highly similar to that of VGAM17, is marked by an underline within the sequence of VGAM17 PRECURSOR RNA.

Reference is now made to FIG. 17C, which shows the secondary folding of VGAM17 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM17 FOLDED PRECURSOR RNA, both of FIG. 17A. A probable (>28%) nucleotide sequence of VGAM17 RNA, designated SEQ ID:23 of FIG. 17B, is marked by an underline on VGAM17 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 17D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM17, each binding site corresponding to HOST BINDING SITE of FIG. 17A, and their complementarity to SEQ ID:23, which is highly likely (>28%) to be identical or highly similar to the nucleotide sequence of VGAM17 RNA of FIG. 17A.

As mentioned hereinabove with reference to FIG. 17A a function of VGAM17 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A. It is appreciated that specific functions, and accordingly utilities, of VGAM17 correlate with, and may be deduced from, the identity of the host target genes which VGAM17 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to CNR1 BINDING SITE. cannabinoid receptor 1 (brain) (CNR1) is a host target gene of VGAM17, corresponding to VGAM17-HOST TARGET GENE of FIG. 17A. CNR1 BINDING SITE is a host binding site found in the 3′ untranslated region of CNR1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of CNR1 BINDING SITE, designated SEQ ID:24, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

A function of VGAM17 is therefore inhibition of cannabinoid receptor 1 (brain) (CNR1), a host gene which encodes a receptor that is involved in the cannabinoid-induced CNS effects., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of CNR1 has been established by previous studies. Ledent et al. (1999) investigated the function of the central cannabinoid receptor (CB1) by disrupting the gene in mice. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of CB1 in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggested that CB1 is involved in the motivational properties of opiates and in the development of physical dependence, and extended the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior The cannabinoids are psychoactive ingredients of marijuana, principally delta-9-tetrahydrocannabinol, as well as the synthetic analogs. Matsuda et al. (1990) cloned a cannabinoid receptor from a rat brain. Gerard et al. (1991) isolated a cDNA encoding a cannabinoid receptor from a human brain stem cDNA library. The deduced amino acid sequence encoded a protein of 472 residues which shared 97.3% identity with the rat cannabinoid receptor cloned by Matsuda et al. (1990). They provided evidence for the existence of an identical cannabinoid receptor expressed in human testis

Animal model experiments lend further support to the function of CNR1. Di Marzo et al. (2001) showed that following temporary food restriction, CB1 receptor knockout mice eat less than their wildtype littermates, and the CB1 antagonist SR141716A reduces food intake in wildtype but not knockout mice. Furthermore, defective leptin (164160) signaling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. Di Marzo et al. (2001) concluded that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin

It is appreciated that the abovementioned animal model for CNR1 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   edent, C.; Valverde, O.; Cossu, G.; Petitet, F.; Aubert, J.-F.;     Beslot, F.; Bohme, G. A.; Imperato, A.; Pedrazzini, T.; Rogues, B.     P.; Vassart, G.; Fratta, W.; Parmentier, M.: Unresponsiveness to     cannabinoids and reduced addictive effects of opiates in CB(1)     receptor knockout mice. Science 283: 401-404, 1999. PubMed ID:     9888857 2. Gerard, C. M.; Mollereau, C.; Vassart, G.; Parmentier,     M.: Molecular cloning of a human cannabinoid receptor which is also     expressed in testis. Biochem. J. 279: 129-134, 1991.

Further studies establishing the function and utilities of CNR1 are found in John Hopkins OMIM database record ID 114610, and in references numbered 8-15 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylglucosaminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylglucosaminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylglucosaminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylglucosaminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM17, corresponding to VGAM17-HOST-TARGET GENE of FIG. 17A. EXTL1 BINDING SITE is a host binding site found in the 3′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 17A. FIG. 17D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:25, to the nucleotide sequence of VGAM17 RNA of FIG. 17A, designated SEQ ID:23.

Yet another function of VGAM17 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM17 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to FIG. 18A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 18 (VGAM18) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM18 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM18 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM18 GENE is a viral gene contained in the genome of Equine herpesvirus 2. VGAM18-HOST TARGET GENE is a human gene contained in the human genome.

VGAM18 GENE encodes a VGAM18 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM18, VGAM18 PRECURSOR RNA, does not encoded a protein.

VGAM18 PRECURSOR RNA folds onto itself, forming VGAM18 FOLDED PRECURSOR RNA. As FIG. 18 illustrates, VGAM18 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM18 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM18 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM18-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM18-HOST-TARGET RNA. VGAM18-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM18 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM18-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM18 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 18A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM18 RNA to HOST BINDING SITE inhibits translation of VGAM18-HOST-TARGET RNA into VGAM18-HOST-TARGET PROTEIN. VGAM18-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM18-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM18. The mRNA of each of this plurality of host target genes of VGAM18 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM18 RNA, and which when bound by VGAM18 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM18. The plurality of host target genes of VGAM18 and their respective host binding sites, are described hereinbelow with reference to FIG. 18D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 18A with specific reference to translational inhibition exerted by VGAM18 on one or more host target genes of VGAM18, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM18 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

Reference is now made to FIG. 18B which shows the nucleotide sequence of VGAM18 PRECURSOR RNA of FIG. 18A, designated SEQ ID:39, and a probable nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40. The nucleotide sequence of SEQ ID:40, which is highly likely (over 35%) to be identical or highly similar to that of VGAM18, is marked by an underline within the sequence of VGAM18 PRECURSOR RNA.

Reference is now made to FIG. 18C, which shows the secondary folding of VGAM18 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM18 FOLDED PRECURSOR RNA, both of FIG. 18A. A probable (>35%) nucleotide sequence of VGAM18 RNA, designated SEQ ID:40 of FIG. 18B, is marked by an underline on VGAM18 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 18D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM18, each binding site corresponding to HOST BINDING SITE of FIG. 18A, and their complementarity to SEQ ID:40, which is highly likely (>35%) to be identical or highly similar to the nucleotide sequence of VGAM18 RNA of FIG. 18A.

As mentioned hereinabove with reference to FIG. 18A a function of VGAM18 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2. It is appreciated that specific functions, and accordingly utilities, of VGAM18 correlate with, and may be deduced from, the identity of the host target genes which VGAM18 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to DIAPH2 BINDING SITE. diaphanous (Drosophila, homolog) 2 (DIAPH2) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. DIAPH2 BINDING SITE is a host binding site found in the 3′ untranslated region of DIAPH2, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of DIAPH2 BINDING SITE, designated SEQ ID:41, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A function of VGAM18 is therefore inhibition of diaphanous (Drosophila, homolog) 2 (DIAPH2), a host gene which encodes a Protein that may affect in oogenesis and is associated with premature ovarian failure, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DIAPH2 has been established by previous studies. Mutant alleles of Drosophila dia affect spermatogenesis or oogenesis and lead to sterility. Bione et al. (1998) characterized a human homolog of ‘diaphanous’ and demonstrated that this gene, designated DIA, is interrupted by a breakpoint in a patient with familial premature ovarian failure (POF; 311360). A human EST, DRES25, which showed significant homology with the Drosophila gene, was mapped to Xq22 by fluorescence in situ hybridization. Bione et al. (1998) found that the human DIA open reading frame encodes a 1,101-amino acid protein approximately 39% identical to the Drosophila protein. Northern blot analysis of human adult and fetal tissues detected 4 transcripts, 3 of which are expressed ubiquitously and the fourth exclusively in adult testis. Bione et al. (1998) showed that the DIA gene is expressed in developing ovaries and testis of the mouse, as well as in all other tissues, from the E16 stage. Banfi et al. (1997) had indicated that a human homolog of ‘diaphanous’ maps to Xq22. Lynch et al. (1997) noted that a nonsyndromic form of X-linked deafness, DFN2 (304500), also maps to Xq22, making this homologous gene a candidate for DFN2 hearing loss. In the family of patient BC studied by Sala et al. (1997), a balanced X;12 translocation, t(X;12)(q21;p1.3), was associated with premature ovarian failure (311360). Patient BC had secondary amenorrhea, with no other associated features, at the age of 17 years. Her mother, who carried the same chromosomal rearrangement, was diagnosed with premature menopause at the age of 32 years. At diagnosis, both mother and daughter had high gonadotropin levels and inactivation of the normal X chromosome (Philippe et al., 1993). The breakpoint was mapped, by FISH, to a specific YAC. The translocation breakpoint was found to be in the last 200-kb intron of the gene.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ione, S.; Sala, C.; Manzini, C.; Arrigo, G.; Zuffardi, O.; Banfi,     S.; Borsani, G.; Jonveaux, P.; Philippe, C.; Zuccotti, M.; Ballabio,     A.; Toniolo, D.: A human homologue of the Drosophila melanogaster     diaphanous gene is disrupted in a patient with premature ovarian     failure: evidence for conserved function in oogenesis and     implications for human sterility. Am. J. Hum. Genet. 62:     533-541, 1998. PubMed ID: 9497258 5. Philippe, C.; Cremers, F. P.     M.; Chery, M.; Bach, I.; Abbadi, N.; Ropers, H. H.; Gilgenkrantz,     S.: Physical mapping of DNA markers in the q13-q22 region of the     human X chromosome. Genomics 17: 147-152, 1993.

Further studies establishing the function and utilities of DIAPH2 are found in John Hopkins OMIM database record ID 300108, and in references numbered 20-25 listed hereinbelow.

Reference is now made to EPHB2 BINDING SITE. EphB2 (EPHB2) is a host target gene of VGAM18, corresponding to VGAM18-HOST TARGET GENE of FIG. 18A. EPHB2 BINDING SITE is a host binding site found in the 3′ untranslated region of EPHB2, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of EPHB2 BINDING SITE, designated SEQ ID:42, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

Yet another function of VGAM18 is therefore inhibition of EphB2 (EPHB2), a host gene which encodes a receptor that Eph-related receptor tyrosine kinase B2; may have a role in neurogenesis., as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of EPHB2 has been established by previous studies. See 179610 for background on Eph receptors and their ligands, the ephrins. Chan and Watt (1991) cloned partial sequences of the EEK (EPHA8; 176945) and ERK genes encoding members of the EPH subclass of receptor protein-tyrosine kinases. Northern blot analysis of rat RNA showed that DNA encoding human ERK hybridized to transcripts most abundantly in lung. By screening a human fetal brain cDNA expression library using a monoclonal antiphosphotyrosine antibody and by 5-prime RACE (rapid amplification of cDNA ends) procedures, Ikegaki et al. (1995) isolated overlapping cDNAs encoding a receptor-type tyrosine kinase belonging to the EPH family and designated the gene DRT (for developmentally regulated EPH-related tyrosine kinase). The DRT gene is expressed in transcripts of 3 different sizes (4, 5, and 11 kb). The DRT transcripts are expressed in human brain and several other tissues, including heart, lung, kidney, placenta, pancreas, liver, and skeletal muscle, but the 11-kb DRT transcript is preferentially expressed in fetal brain. Steady-state levels of DRT mRNA in several tissues, including brain, heart, lung, and kidney, are greater in the midterm fetus than those in the adult. Ikegaki et al. (1995) showed that a large number of tumor cell lines derived from neuroectoderm express DRT transcripts. The authors speculated that DRT may play a part in human neurogenesis. Using a yeast 2-hybrid system, Cowan et al. (2000) demonstrated that PDZ domain-containing protein Pick1 (PRKCABP; 605926) binds the C-terminal tail of EphB2. Using colocalization studies and biochemical analysis, they demonstrated that a protein complex containing EphB2 and aquaporin-1 (AQP1; 107776) is formed in vivo. They concluded that Ephb2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water. Chan and Watt (1991) mapped the EEK and ERK genes to chromosome 1 by Southern blot analysis of somatic cell hybrids. Ikegaki et al. (1995) mapped DRT, the EPHB2 gene, to 1p36.1-p35 by PCR screening of human/rodent somatic cell hybrid panels and by fluorescence in situ hybridization. As the distal end of 1p is often deleted in neuroblastomas, the DRT gene may play a role in neuroblastoma and small cell lung carcinoma (SCLC) tumorigenesis. By fluorescence in situ hybridization, Saito et al. (1995) demonstrated that the ERK gene is located in chromosomal region 1p36.1. They showed that the homologous genes are located on mouse 4D2.2-D3 and rat 5q36.13, both of which are regions with conserved linkage homology to human chromosome 1p.

Animal model experiments lend further support to the function of EPHB2. Halford et al. (2000) generated mice deficient in Ryk (600524) and found that they had a distinctive craniofacial appearance, shortened limbs, and postnatal mortality due to feeding and respiratory complications associated with a complete cleft of the secondary palate. Consistent with cleft palate phenocopy in Ephb2/Ephb3 (601839)-deficient mice and the role of a Drosophila Ryk ortholog, ‘Derailed,’ in the transduction of repulsive axon pathfinding cues, biochemical data implicated Ryk in signaling mediated by Eph receptors and cell junction-associated Af6 (159559). Halford et al. (2000) concluded that their findings highlighted the importance of signal crosstalk between members of different RTK subfamilies.

It is appreciated that the abovementioned animal model for EPHB2 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Ikegaki, N.; Tang, X. X.; Liu, X.-G.; Biegel, J. A.; Allen, C.;     Yoshioka, A.; Sulman, E. P.; Brodeur, G. M.; Pleasure, D. E.:     Molecular characterization and chromosomal localization of DRT     (EPHT3): a developmentally regulated human protein-tyrosine kinase     gene of the EPH family. Hum. Molec. Genet. 4: 2033-2045, 1995.     PubMed ID: 8589679 6. Halford, M. M.; Armes, J.; Buchert, M.;     Meskenaite, V.; Grail, D.; Hibbs, M. L.; Wilks, A. F.; Farlie, P.     G.; Newgreen, D. F.; Hovens, C. M.; Stacker, S. A.: Ryk-deficient     mice exhibit craniofacial defects associated with perturbed Eph     receptor crosstalk. Nature Genet. 25: 414-418, 2000.

Further studies establishing the function and utilities of EPHB2 are found in John Hopkins OMIM database record ID 600997, and in references numbered 4 and 26-37 listed hereinbelow.

Reference is now made to LYN BINDING SITE. v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN) is a host target gene of VGAM18, corresponding to VGAM18-HOST TARGET GENE of FIG. 18A. LYN BINDING SITE is a host binding site found in the 3′ untranslated region of LYN, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of LYN BINDING SITE, designated SEQ ID:43, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

An additional function of VGAM18 is therefore inhibition of v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN), a host gene which encodes a transcripition factor that is a Tyrosine kinase with similarity to murine tyrosine kinase p56lck; similar to v-yes protein and the gene products of v-fgr and v-src, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of LYN has been established by previous studies. Parravicini et al. (2002) noted that Lyn deficiency impairs some mast cell functions, but degranulation and cytokine production are intact. In Gab2 (606203)-deficient mice, on the other hand, degranulation and cytokine production are impaired. Using immunoblot analysis, they showed that although Lyn is essential for Syk (600085) activation and Lat (602354) phosphorylation after Fcer1 (see FCER1G; 147139) aggregation, neither Lyn nor Lat are necessary for Gab2 phosphorylation. RT-PCR and coimmunoprecipitation analyses demonstrated abundant Fyn (137025) expression in mast cells and an association with Gab2. In cells lacking Fyn, neither Gab2 nor Akt (164730) were phosphorylated. Functional analysis showed that Lyn −/− mast cells exhibited hyperdegranulation and enhanced PI3K (see 601232) activity and Akt phosphorylation, whereas in Fyn −/− mast cells the degranulation response was inhibited. The inhibition was associated with decreased binding of PI3K with Gab2. Parravicini et al. (2002) observed that the degranulation response was independent of Fcer1 stimulation in Fyn-deficient mast cells and that degranulation was dependent on PI3K in wildtype and mutant cell lines. The degranulation response was dependent on a rise in intracellular calcium that was inhibited in Lyn-deficient mast cells but intact in Fyn-deficient cells. Degranulation proceeded in Lyn −/− cells due to increased activation and constitutive phosphorylation of the calcium-independent protein kinase C delta isoform (PRKCD; 176977). Parravicini et al. (2002) concluded that Fyn- and Lyn-initiated pathways synergize in late events at the level of protein kinase C and calcium, respectively, to regulate mast cell degranulation.

Animal model experiments lend further support to the function of LYN. Hibbs et al. (1995) demonstrated that mice homozygous for a disruption of the Lyn locus display abnormalities associated with the B-lymphocyte lineage and in mast cell function. Despite reduced numbers of recirculating B lymphocytes, the homozygous deficient mice are immunoglobulin M hyperglobulinemic. Lyn-deficient mice show IgM hyperglobulinemia. Immune responses to T-independent and T-dependent antigens were affected. The deficient mice failed to mediate an allergic response to IgE cross-linking, indicating that activation of Lyn plays an indispensable role in signaling by the high-affinity IgE receptor (FCER). Homozygous deficient mice had circulating autoreactive antibodies, and many showed severe glomerulonephritis caused by the deposition of IgG immune complexes in the kidney, a pathology reminiscent of systemic lupus erythematosus. Hibbs et al. (1995) stated that, collectively, these results implicated LYN as having an indispensable role in immunoglobulin-mediated signaling, particularly in establishing B cell tolerance. Harder et al. (2001) generated mice with a gain-of-function Lyn mutation (tyr508 to phe, which they referred to as ‘up’) analogous to the tyr527-to-phe activating mutation in the mouse Src gene (190090) (Webster et al., 1995). Even aging mice with the Lyn up/up phenotype did not display hematologic malignancies, unlike Lyn −/− mice, which developed splenomegaly, increased myeloid progenitors, and monocyte/macrophage tumors. Biochemical analysis revealed that Lyn is essential in establishing ITIM (immunoreceptor tyrosine-based inhibitory motif)-dependent signaling and for the activation of specific protein tyrosine phosphatases within myeloid cells, which may underlie the susceptibility of Lyn −/− mice to tumorigenesis. Hasegawa et al. (2001) generated mice deficient in both Cd19 (107265) and Lyn. Cd19 deficiency

It is appreciated that the abovementioned animal model for LYN is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Harder, K. W.; Parsons, L. M.; Armes, J.; Evans, N.; Kountouri, N.;     Clark, R.; Quillici, C.; Grail, D.; Hodgson, G. S.; Dunn, A. R.;     Hibbs, M. L.: Gain- and loss-of-function Lyn mutant mice define a     critical inhibitory role for Lyn in the myeloid lineage. Immunity     15: 603-615, 2001. PubMed ID: 11672542 Parravicini, V.; Gadina, M.;     Kovarova, M.; Odom, S.; Gonzalez-Espinosa, C.; Furumoto, Y.; Saitoh,     S.; Samelson, L. E.; O'Shea, J. J.; Rivera, J.: Fyn kinase initiates     complementary signals required for IgE-dependent mast cell     degranulation. Nature Immun. 3: 741-748, 2002.

Further studies establishing the function and utilities of LYN are found in John Hopkins OMIM database record ID 165120, and in references numbered 38-43 listed hereinbelow.

Reference is now made to NRIP1 BINDING SITE. nuclear receptor interacting protein 1 (NRIP1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. NRIP1 BINDING SITE is a host binding site found in the 3′ untranslated region of NRIP1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of NRIP1 BINDING SITE, designated SEQ ID:44, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of nuclear receptor interacting protein 1 (NRIP1), a host gene which encodes a Protein that modulates transcriptional activation by the estrogen receptor., as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of NRIP1 has been established by previous studies. Cavailles et al. (1995) identified the receptor-interacting protein 140 (RIP140) by virtue of its direct association with a transcriptional activation domain of the estrogen receptor (ESR; 133430) in the presence of estrogen; by fluorescence in situ hybridization with a cDNA clone, they mapped the gene to 21q11. Katsanis et al. (1998) used hybrids, YACs, and PACs to place the RIP140 gene on the physical map of chromosome 21; 21q11 is a gene-poor region.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   availles, V.; Dauvois, S.; Horset, L. F.; Lopez, G.; Hoare, S.;     Kushner, P. J.; Parker, M. G.: Nuclear factor RIP140 modulates     transcriptional activation by the estrogen receptor. EMBO J. 14:     3741-3751, 1995. PubMed ID: 7641693 2. Katsanis, N.; Ives, J. H.;     Groet, J.; Nizetic, D.; Fisher, E. M. C.: Localisation of receptor     interacting protein 140 (RIP140) within 100 kb of D21S13 on 21q11, a     gene-poor region of the human genome. Hum. Genet. 102: 221-223,     1998.

Further studies establishing the function and utilities of NRIP1 are found in John Hopkins OMIM database record ID 602490, and in references numbered 44-45 listed hereinbelow.

Reference is now made to PCTP BINDING SITE. phosphatidylcholine transfer protein (PCTP) is a host target gene of VGAM18, corresponding to VGAM18-HOST TARGET GENE of FIG. 18A. PCTP BINDING SITE is a host binding site found in the 3′ untranslated region of PCTP, corresponding to HOST BINDING SITE of FIG. 18A.

FIG. 18D illustrates the complementarity of the nucleotide sequence of PCTP BINDING SITE, designated SEQ ID:45, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

Yet a further function of VGAM18 is therefore inhibition of phosphatidylcholine transfer protein (PCTP), a host gene which encodes a Enzyme that catalyzes the transfer of phosphatidylcholine between membranes (by similarity)., as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of PCTP has been established by previous studies. Phosphatidylcholine (PC) transfer protein (PCTP) is a cytosolic protein first purified from bovine and rat liver that catalyzes intermembrane transfer of PC. By searching an EST database for homologs of bovine Pctp, followed by 5-prime RACE and PCR of a kidney cDNA library, Cohen et al. (1999) obtained a cDNA encoding human PCTP. The deduced 214-amino acid human protein is 76% and 80% identical to bovine and rat Pctp, respectively. Northern blot analysis revealed wide expression of an approximately 2.3-kb PCTP transcript in all tissues tested except thymus. Highest expression was detected in liver, placenta, testis, kidney, and heart, and lowest levels were found in brain and lung.

Animal model experiments lend further support to the function of PCTP. Van Helvoort et al. (1999) disrupted the Pctp gene in mice. Pctp knockout mice showed no defects in the secretion of PC into bile or lung surfactant, and the lipid content and composition of bile and surfactant was normal. The authors concluded that PCTP does not play a major role in transporting PC from the endoplasmic reticulum, where it is synthesized, to the hepatocyte canalicular membrane.

It is appreciated that the abovementioned animal model for PCTP is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ohen, D. E.; Green, R. M.; Wu, M. K.; Beier, D. R.: Cloning,     tissue-specific expression, gene structure and chromosomal     localization of human phosphatidylcholine transfer protein. Biochim.     Biophys. Acta 1447: 265-270, 1999. PubMed ID: 10542325 2. van     Helvoort, A.; de Brouwer, A.; Ottenhoff, R.; Brouwers, J. F. H. M.;     Wijnholds, J.; Beijnen, J. H.; Rijneveld, A.; van der Valk, M. A.;     Majoor, D.; Voorhout, W.; Wirtz, K. W. A.; Elferink, R. P. J. O.;     Borst, P.: Mice without phosphatidylcholine transfer protein have no     defects in the secretion of phosphatidylcholine into bile or into     lung airspaces. Proc. Nat. Acad. Sci. 96: 11501-11506, 1999.

Further studies establishing the function and utilities of PCTP are found in John Hopkins OMIM database record ID 606055, and in references numbered 46-47 listed hereinbelow.

Reference is now made to SMAP BINDING SITE. skeletal muscle abundant protein (SMAP) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. SMAP BINDING SITE is a host binding site found in the 3′ untranslated region of SMAP, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of SMAP BINDING SITE, designated SEQ ID:46, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

Another function of VGAM18 is therefore inhibition of skeletal muscle abundant protein (SMAP), a host gene which encodes a Protein that is required maternally for proper expression of other homeotic genes, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of SMAP has been established by previous studies. Using a yeast 2-hybrid system, Shimizu et al. (1996) isolated the gene encoding a protein which interacts with smg GDS (see 179502) and named it SMAP, for ‘smg GDS-associated protein.’ The cDNA encodes a 792-amino acid polypeptide containing 9 Armadillo repeats, found in the Drosophila ‘Armadillo’ protein and implicated in protein-protein interactions. SMAP protein is phosphorylated by v-src (SRC; 190090), and this phosphorylation reduces the affinity of SMAP for smg GDS. Northern blot and tissue distribution analyses revealed that SMAP is expressed ubiquitously and is highly concentrated in the endoplasmic reticulum. Shimizu et al. (1996) also noted that SMAP is homologous to the sea urchin gene SpKAP115, an accessory subunit of sea urchin kinesin

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Shimizu, K.; Kawabe, H.; Minimi, S.; Honda, T.; Takaishi, K.;     Shirataki, H.; Takai, Y.: SMAP, an 5 mg GDS-associating protein     having arm repeats and phosphorylated by Src tyrosine kinase. J.     Biol. Chem. 271: 27013-27017, 1996.

Further studies establishing the function and utilities of SMAP are found in John Hopkins OMIM database record ID 601836, and in references numbered 48 listed hereinbelow.

Reference is now made to SORCS1 BINDING SITE. (SORCS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. SORCS1 BINDING SITE is a host binding site found in the 3′ untranslated region of SORCS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of SORCS1 BINDING SITE, designated SEQ ID:47, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

Yet another function of VGAM18 is therefore inhibition of (SORCS1), a host gene which encodes a Protein that is a member of the VPS10 domain containing receptor family, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of SORCS1 has been established by previous studies. The VPS10 domain-containing receptors, including sortilin (SORT1; 602458) and sortilin-related receptor (SORL1; 602005), derive their name from the yeast vacuolar protein sorting protein-10, which is involved in sorting of carboxy-peptidase Y from the Golgi apparatus to the vacuole. By EST database searching with mouse sequence of 2 VPS10 proteins, S or CS1 and SorCS2 (606284) (Hermey et al., 1999; Rezgaoui et al., 2001), Hampe et al. (2001) identified 3 novel human VPS10 domain-containing receptors. Two were orthologs of mouse SORCS1 and SORCS2; the third was designated SORCS3 (606285). Hampe et al. (2001) noted that all mammalian VPS10 domains carry an N-terminal signal peptide for translocation into the endoplasmic reticulum. The greatest similarity between the receptors is found in the C-terminal parts of the VPS10 domains, which harbor 12 cysteine residues with a characteristic spacing conserved in all VPS10 proteins from yeast to man. SORCS1 and SORCS3 share the greatest homology. SORCS2 shares the same domain composition, but is less similar. SORT1 and SORTL1 lack the leucine-rich domain of the SORCS proteins, and their VPS10 domains are less related.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Rezgaoui, M.; Hermey, G.; Riedel, I. B.; Hampe, W.; Schaller, H. C.;     Hermans-Borgmeyer, I.: Identification of S or CS2, a novel member of     the VPS10 domain containing receptor family, prominently expressed     in the developing mouse brain. Mech. Dev. 100: 335-338, 2001.

Further studies establishing the function and utilities of SORCS1 are found in John Hopkins OMIM database record ID 606283, and in references numbered 49-51 listed hereinbelow.

Reference is now made to TIMP3 BINDING SITE. tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseu (TIMP3) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TIMP3 BINDING SITE is a host binding site found in the 5′ untranslated region of TIMP3, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TIMP3 BINDING SITE, designated SEQ ID:48, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

An additional function of VGAM18 is therefore inhibition of tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseu (TIMP3), a host gene which encodes a Protein that is associated with Sorsby's fundus dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TIMP3 has been established by previous studies. Osman et al. (2002) showed that mature dendritic cells (DCs) produce more MMP9 (120361) than do immature DCs, facilitating their hydroxaminic acid-inhibitable migration through gel in vitro and, presumably, through the extracellular matrix to monitor the antigenic environment in vivo. RT-PCR analysis indicated that the enhanced expression of MMP9 is correlated with a downregulation of TIMP1 and, particularly, TIMP2, while expression of TIMP3 is upregulated. The authors concluded that the balance of MMP and TIMP determines the net migratory capacity of DCs. They proposed that TIMP3 may be a marker for mature DCs. Langton et al. (1998) found that wildtype TIMP3 is localized entirely to the extracellular matrix (ECM) in both its glycosylated (27 kD) and unglycosylated (24 kD) forms. A COOH-terminally truncated TIMP3 molecule was found to be a non-ECM-bound matrix metalloproteinase (MMP) inhibitor, whereas a chimeric TIMP molecule, consisting of the NH2-terminal domain of TIMP2 fused to the COOH-terminal domain of TIMP3, displayed ECM binding, albeit with a lower affinity than the wildtype TIMP3 molecule. Thus, as in TIMP1 and TIMP2, the NH2-terminal domain is responsible for MMP inhibition, whereas the COOH-terminal domain is most important in mediating the specific functions of the molecule. A mutant TIMP3 in which serine-181 was changed to cysteine (188826.0001), found in Sorsby fundus dystrophy, gave rise to an additional 48-kD species (possibly a TIMP3 dimer) that retained its ability to inhibit MMPs and localize to the ECM when expressed in COS-7 cells. These data favored the hypothesis that the TIMP3 mutation seen in Sorsby fundus dystrophy contributes to disease progression by accumulation of mutant protein rather than by loss of functional TIMP3. Weber et al. (1994), who had mapped the gene for Sorsby fundus dystrophy (SFD; 1136900) to 22q13-qter, examined the TIMP3 gene as a possible site of causative mutations in SFD on the basis of its chromosomal location and its pivotal role in extracellular matrix remodeling. They identified point mutations in TIMP3 in affected members of 2 SFD pedigrees. These mutations were predicted to disrupt the tertiary structure and thus the functional properties of the mature protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   sman, M.; Tortorella, M.; Londei, M.; Quaratino, S.: Expression of     matrix metalloproteinases and tissue inhibitors of     metalloproteinases define the migratory characteristics of human     monocyte-derived dendritic cells. Immunology 105: 73-82, 2002.     PubMed ID: 11849317 11. Weber, B. H. F.; Vogt, G.; Pruett, R. C.;     Stohr, H.; Felbor, U.: Mutations in the tissue inhibitor     metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus     dystrophy. Nature Genet. 8: 352-356, 1994.

Further studies establishing the function and utilities of TIMP3 are found in John Hopkins OMIM database record ID 188826, and in references numbered 52-64 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to TRPS1 BINDING SITE. trichorhinophalangeal syndrome I (TRPS1) is a host target gene of VGAM18, corresponding to VGAM18-HOST-TARGET GENE of FIG. 18A. TRPS1 BINDING SITE is a host binding site found in the 3′ untranslated region of TRPS1, corresponding to HOST BINDING SITE of FIG. 18A. FIG. 18D illustrates the complementarity of the nucleotide sequence of TRPS1 BINDING SITE, designated SEQ ID:49, to the nucleotide sequence of VGAM18 RNA of FIG. 18A, designated SEQ ID:40.

A further function of VGAM18 is therefore inhibition of trichorhinophalangeal syndrome I (TRPS1), a host gene which encodes a transcripition factor that is associated with trichorhinophalangeal syndrome type I, type III, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM18 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of TRPS1 has been established by previous studies. Trichorhinophalangeal syndrome type I (190350) is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant. TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 gene to 8q24. It maps centromeric to the gene that is mutant in multiple exostoses type I (EXT1; 133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses. Momeni et al. (2000) positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with TRPS I and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, has 7 exons and encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals and an unusual combination of different zinc finger motifs, including IKAROS-like (see 603023) and GATA-binding (see 600576) sequences. Momeni et al. (2000) identified 6 different nonsense mutations in 10 unrelated patients. The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III (190351) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe bradycardia, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of Ludecke et al. (2001), 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Momeni, P.; Glockner, G.; Schmidt, O.; von Holtum, D.; Albrecht, B.;     Gillessen-Kaesbach, G.; Hennekam, R.; Meinecke, P.; Zabel, B.;     Rosenthal, A.; Horsthemke, B.; Ludecke, H.-J.: Mutations in a new     gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal     syndrome type I. Nature Genet. 24: 71-74, 2000. PubMed ID: 10615131     Ludecke, H.-J.; Schaper, J.; Meinecke, P.; Momeni, P.; Gross, S.;     von Holtum, D.; Hirche, H.; Abramowicz, M. J.; Albrecht, B.; Apacik,     C.; Christen, H.-J.; Claussen, U.; and 28 others: Genotypic and     phenotypic spectrum in tricho-rhino-phalangeal syndrome types I     and III. Am. J. Hum. Genet. 68: 81-91, 2001.

Further studies establishing the function and utilities of TRPS1 are found in John Hopkins OMIM database record ID 604386, and in references numbered 65-71 listed hereinbelow.

Reference is now made to FIG. 19A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 19 (VGAM19) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM19 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM19 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM19 GENE is a viral gene contained in the genome of Alcelaphine herpesvirus 1. VGAM19-HOST TARGET GENE is a human gene contained in the human genome.

VGAM19 GENE encodes a VGAM19 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM19, VGAM19 PRECURSOR RNA, does not encoded a protein.

VGAM19 PRECURSOR RNA folds onto itself, forming VGAM19 FOLDED PRECURSOR RNA. As FIG. 19 illustrates, VGAM19 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM19 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM19 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM19-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM19-HOST-TARGET RNA. VGAM19-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM19 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM19-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM19 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 19A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM19 RNA to HOST BINDING SITE inhibits translation of VGAM19-HOST-TARGET RNA into VGAM19-HOST-TARGET PROTEIN. VGAM19-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM19-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM19. The mRNA of each of this plurality of host target genes of VGAM19 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM19 RNA, and which when bound by VGAM19 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM19. The plurality of host target genes of VGAM19 and their respective host binding sites, are described hereinbelow with reference to FIG. 19D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 19A with specific reference to translational inhibition exerted by VGAM19 on one or more host target genes of VGAM19, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM19 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

Reference is now made to FIG. 19B which shows the nucleotide sequence of VGAM19 PRECURSOR RNA of FIG. 19A, designated SEQ ID:65, and a probable nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66. The nucleotide sequence of SEQ ID:66, which is highly likely (over 35%) to be identical or highly similar to that of VGAM19, is marked by an underline within the sequence of VGAM19 PRECURSOR RNA.

Reference is now made to FIG. 19C, which shows the secondary folding of VGAM19 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM19 FOLDED PRECURSOR RNA, both of FIG. 19A. A probable (>35%) nucleotide sequence of VGAM19 RNA, designated SEQ ID:66 of FIG. 19B, is marked by an underline on VGAM19 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 19D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM19, each binding site corresponding to HOST BINDING SITE of FIG. 19A, and their complementarity to SEQ ID:66, which is highly likely (>35%) to be identical or highly similar to the nucleotide sequence of VGAM19 RNA of FIG. 19A.

As mentioned hereinabove with reference to FIG. 19A a function of VGAM19 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1. It is appreciated that specific functions, and accordingly utilities, of VGAM19 correlate with, and may be deduced from, the identity of the host target genes which VGAM19 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to DLG5 BINDING SITE. discs, large (Drosophila) homolog 5 (DLG5) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. DLG5 BINDING SITE is a host binding site found in the 3′ untranslated region of DLG5, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of DLG5 BINDING SITE, designated SEQ ID:67, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

a function of VGAM19 is therefore inhibition of discs, large (Drosophila) homolog 5 (DLG5), a host gene which encodes a Protein that may transmit extracellular signals to inhibit cell proliferation., as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of DLG5 has been established by previous studies. Vertebrate homologs of the Drosophila discs large (dlg) gene are members of the MAGUK (membrane-associated guanylate kinase) family. See 602887. MAGUK proteins contain PDZ motifs, an SH3 domain, and a guanylate kinase (GUK)-homologous region. Both the PDZ and GUK domains are thought to contribute to protein-protein interactions. By searching an EST database for sequences related to Drosophila dlg, Nakamura et al. (1998) identified cDNAs encoding a novel human homolog. Northern blot analysis revealed that the 9.4-kb transcript was highly expressed in placenta and prostate, as well as in several other tissues, leading the authors to designate the gene PDLG (placenta and prostate DLG). An additional 8.8-kb PDLG mRNA was detected in thyroid. The predicted 859-amino acid PDLG protein contains 3 PDZ domains, an SH3 domain, and a GUK region. PDLG is 45% and 40% identical to DLG1 (601014) and Drosophila dlg, respectively. Western blot analysis of extracts of human prostate tissue and various cell lines showed that PDLG has an apparent molecular mass of 105 kD. Immunofluorescence experiments indicated that PDLG is localized at the plasma membrane and cytoplasm, and is expressed in the gland epithelial cells of normal prostate tissue but not in prostate cell lines. Using a yeast 2-hybrid screen, Nakamura et al. (1998) determined that PDLG interacts with the GUK domain of p55 (MPP1; 305360), a palmitoylated erythrocyte membrane MAGUK protein. The authors suggested that PDLG and p55 form a heteromeric MAGUK complex at the plasma membrane and cluster various intracellular molecules to play roles in maintaining the structure of epithelial cells and transmitting extracellular signals to the membrane and cytoskeleton. Independently, Nagase et al. (1998) identified KIAA0583, a DLG5 cDNA. By radiation hybrid analysis, they mapped the DLG5 gene to chromosome 10. Using the same technique, Nakamura et al. (1998) refined the localization of the DLG5 gene to 10q23.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Miyajima, N.; Tanaka, A.; Kotani, H.;     Nomura, N.; Ohara, O.: Prediction of the coding sequences of     unidentified human genes. IX. The complete sequences of 100 new cDNA     clones from brain which can code for large proteins in vitro. DNA     Res. 5: 31-39, 1998. PubMed ID: 9628581 2. Nakamura, H.; Sudo, T.;     Tsuiki, H.; Miyake, H.; Morisaki, T.; Sasaki, J.; Masuko, N.; Kochi,     M.; Ushio, Y.; Saya, H.: Identification of a novel human homolog of     the Drosophila dlg, P-dlg, specifically expressed in the gland     tissues and interacting with p55. FEBS Lett. 433: 63-67, 1998.

Further studies establishing the function and utilities of DLG5 are found in John Hopkins OMIM database record ID 604090, and in references numbered 72-73 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to RBBP9 BINDING SITE. retinoblastoma-binding protein 9 (RBBP9) is a host target gene of VGAM19, corresponding to VGAM19-HOST-TARGET GENE of FIG. 19A. RBBP9 BINDING SITE is a host binding site found in the 3′ untranslated region of RBBP9, corresponding to HOST BINDING SITE of FIG. 19A. FIG. 19D illustrates the complementarity of the nucleotide sequence of RBBP9 BINDING SITE, designated SEQ ID:68, to the nucleotide sequence of VGAM19 RNA of FIG. 19A, designated SEQ ID:66.

Yet another function of VGAM19 is therefore inhibition of retinoblastoma-binding protein 9 (RBBP9), a host gene which encodes a Protein that is a retinoblastoma-binding protein and is associated with cancer, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM19 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RBBP9 has been established by previous studies. The retinoblastoma (RB1; 180200) gene is one of the most extensively studied tumor-suppressor genes, in part, perhaps, because it was the first in which the Knudson 2-hit model of tumorigenesis in familial cancer syndromes was established at the molecular level. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma. RB inactivation is also found in other human tumors, such as breast cancer (Lee et al., 1988), small-cell carcinoma of the lung (Yokota et al., 1988), glioblastoma (Venter et al., 1991), and acute lymphoblastic leukemia (Cheng et al., 1990). Loss of RB function is associated with loss of cellular proliferative control; introduction of a wildtype RB can suppress cell growth and tumorigenicity. Woitach et al. (1998) described a new gene, designated BOG (B5T overexpressed gene), which was shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta-1 (TGFB1; 190180), as well as in primary human liver tumors. The Bog protein was found to share homology with other retinoblastoma-binding proteins and contained the RB-binding motif LXCXE. Using the yeast 2-hybrid system and coimmunoprecipitation, Woitach et al. (1998) demonstrated that Bog binds to the RB1 gene product. In vivo, Bog/Rb complexes do not contain E2F1 (189971), and Bog can displace E2F1 from E2F1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta-1. Furthermore, normal RLE cells were rapidly transformed when Bog was continuously overexpressed and formed hepatoblastoma-like tumors when transplanted into nude mice. These data suggested that Bog may be important in the transformation process, in part due to its capacity to transfer resistance to the growth-inhibitory effects of TGF-beta-1 through interaction with RB and the subsequent displacement of E2F1.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   oitach, J. T.; Zhang, M.; Niu, C.-H.; Thorgeirsson, S. S.: A     retinoblastoma-binding protein that affects cell-cycle control and     confers transforming ability. Nature Genet. 19: 371-374, 1998.

Further studies establishing the function and utilities of RBBP9 are found in John Hopkins OMIM database record ID 602908, and in references numbered 74-79 listed hereinbelow.

Reference is now made to FIG. 20A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 20 (VGAM20) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM20 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM20 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM20 GENE is a viral gene contained in the genome of Alcelaphine herpesvirus 1. VGAM20-HOST TARGET GENE is a human gene contained in the human genome.

VGAM20 GENE encodes a VGAM20 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM20, VGAM20 PRECURSOR RNA, does not encoded a protein.

VGAM20 PRECURSOR RNA folds onto itself, forming VGAM20 FOLDED PRECURSOR RNA. As FIG. 20 illustrates, VGAM20 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM20 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM20 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM20-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM20-HOST-TARGET RNA. VGAM20-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM20 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM20-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM20 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 20A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM20 RNA to HOST BINDING SITE inhibits translation of VGAM20-HOST-TARGET RNA into VGAM20-HOST-TARGET PROTEIN. VGAM20-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM20-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM20. The mRNA of each of this plurality of host target genes of VGAM20 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM20 RNA, and which when bound by VGAM20 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM20. The plurality of host target genes of VGAM20 and their respective host binding sites, are described hereinbelow with reference to FIG. 20D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 20A with specific reference to translational inhibition exerted by VGAM20 on one or more host target genes of VGAM20, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM20 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

Reference is now made to FIG. 20B which shows the nucleotide sequence of VGAM20 PRECURSOR RNA of FIG. 20A, designated SEQ ID:79, and a probable nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80. The nucleotide sequence of SEQ ID:80, which is highly likely (over 35%) to be identical or highly similar to that of VGAM20, is marked by an underline within the sequence of VGAM20 PRECURSOR RNA.

Reference is now made to FIG. 20C, which shows the secondary folding of VGAM20 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM20 FOLDED PRECURSOR RNA, both of FIG. 20A. A probable (>35%) nucleotide sequence of VGAM20 RNA, designated SEQ ID:80 of FIG. 20B, is marked by an underline on VGAM20 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 20D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM20, each binding site corresponding to HOST BINDING SITE of FIG. 20A, and their complementarity to SEQ ID:80, which is highly likely (>35%) to be identical or highly similar to the nucleotide sequence of VGAM20 RNA of FIG. 20A.

As mentioned hereinabove with reference to FIG. 20A a function of VGAM20 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1. It is appreciated that specific functions, and accordingly utilities, of VGAM20 correlate with, and may be deduced from, the identity of the host target genes which VGAM20 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to FZD7 BINDING SITE. frizzled (Drosophila) homolog 7 (FZD7) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. FZD7 BINDING SITE is a host binding site found in the 3′ untranslated region of FZD7, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of FZD7 BINDING SITE, designated SEQ ID:81, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

A function of VGAM20 is therefore inhibition of frizzled (Drosophila) homolog 7 (FZD7), a host gene which encodes a receptor that enhances beta-catenin mediated signaling., as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of FZD7 has been established by previous studies. Sagara et al. (1998) isolated FZD7 cDNAs from a fetal lung library. They stated that the FZD7 sequence had 20 nucleotide differences compared to that reported for FzE3 by Tanaka et al. (1998), resulting in 9 predicted amino acid substitutions. Sagara et al. (1998) noted that the substituted amino acids are conserved between FZD7 and mouse MHz7. They suggested that the sequence differences between FZD7 and FzE3 resulted from misincorporations during the PCR-based cloning of FzE3. Northern blot analysis revealed that FZD7 is expressed as S— and 4-kb mRNAs in several human tissues, with the highest expression in adult skeletal muscle and fetal kidney. The frizzled-dependent signaling cascade comprises several branches whose differential activation depends on specific Wnt ligands, frizzled receptor isoforms, and the cellular context. In Xenopus embryos, the canonical beta-catenin (116806) pathway contributes to the establishment of the dorsal-ventral axis. A different branch, referred to as the planar cell polarity pathway, is essential for cell polarization during elongation of the axial mesoderm by convergent extension. Winklbauer et al. (2001) demonstrated that a third branch of the cascade is independent of dishevelled (see 601365) function and involves signaling through trimeric G proteins and protein kinase C (PKC, see 176960). During gastrulation, frizzled-7-dependent PKC signaling controls cell-sorting behavior in the mesoderm. Loss of zygotic frizzled-7 function results in the inability of involuted anterior mesoderm to separate from the ectoderm, which leads to severe gastrulation defects. Winklbauer et al. (2001) concluded that their results provide a developmentally relevant in vivo function for the frizzled/PKC pathway in vertebrates.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agara, N.; Toda, G.; Hirai, M.; Terada, M.; Katoh, M.: Molecular     cloning, differential expression, and chromosomal localization of     human frizzled-1, frizzled-2, and frizzled-7. Biochem. Biophys. Res.     Commun. 252: 117-122, 1998. PubMed ID: 9813155 2. Tanaka, S.;     Akiyoshi, T.; Mori, M.; Wands, J. R.; Sugimachi, K.: A novel     frizzled gene identified in human esophageal carcinoma mediates     APC/beta-catenin signals. Proc. Nat. Acad. Sci. 95: 10164-10169,     1998.

Further studies establishing the function and utilities of FZD7 are found in John Hopkins OMIM database record ID 603410, and in references numbered 80-82 listed hereinbelow.

Reference is now made to MMP19 BINDING SITE. matrix metalloproteinase 19 (MMP19) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. MMP19 BINDING SITE is a host binding site found in the 5′ untranslated region of MMP19, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of MMP19 BINDING SITE, designated SEQ ID:82, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of matrix metalloproteinase 19 (MMP19), a host gene which encodes a Enzyme that degrades various components of the extracellular matrix, such as aggrecan and cartilage oligomeric matrix protein (comp), during development, haemostasis and pathological conditions and is associated with arthritic disease, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of MMP19 has been established by previous studies. Pendas et al. (1997) cloned the cDNA for MMP19 from a human liver cDNA library using a combination of homology and direct library screenings. They found that the 508-amino acid protein encoded by this cDNA contains the major structural domains characteristic of MMPs but has a unique insertion and lacks the distinctive structural features of the established MMP subclasses. They therefore proposed that MMP19 represents the first member of a novel MMP subfamily

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Pendas, A. M.; Knauper, V.; Puente, X. S.; Llano, E.; Mattei, M.-G.;     Apte, S.; Murphy, G.; Lopez-Otin, C.: Identification and     characterization of a novel human matrix metalloproteinase with     unique structural characteristics, chromosomal location, and tissue     distribution. J. Biol. Chem. 272: 4281-4286, 1997.

Further studies establishing the function and utilities of MMP19 are found in John Hopkins OMIM database record ID 601807, and in references numbered 83-84 listed hereinbelow.

Reference is now made to MSL3L1 BINDING SITE. male-specific lethal-3 (Drosophila)-like 1 (MSL3L1) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. MSL3L1 BINDING SITE is a host binding site found in the 3′ untranslated region of MSL3L1, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of MSL3L1 BINDING SITE, designated SEQ ID:83, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

An additional function of VGAM20 is therefore inhibition of male-specific lethal-3 (Drosophila)-like 1 (MSL3L1), a host gene which encodes a Protein that is essential for elevating transcription of the single x chromosome in the male., as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of MSL3L1 has been established by previous studies. The Drosophila male-specific lethal (msl) genes regulate transcription from the male X chromosome in a dosage compensation pathway that equalizes X-linked gene expression in males and females. The members of this gene family, including msl1, msl2, msl3, mle, and mof, encode proteins with no sequence similarity to known proteins. However, mutations in each of these genes produce a similar phenotype: sex-specific lethality of male embryos caused by the failure of mutants to increase transcription from the single male X chromosome. The MSL gene products assemble into a multiprotein transcriptional activation complex at hundreds of sites along the chromatin of the X chromosome. By searching sequence databases with the sequence of a BAC clone that maps to Xp22.3, Prakash et al. (1999) identified a human homolog of Drosophila msl3, MSL3-like-1 (MSL3L1). They isolated a cDNA containing a complete MSL3L1 coding sequence. The deduced 521-amino acid MSL3L1 protein shares 30% overall sequence identity with Drosophila MSL3 and 86% identity with mouse Msl311, which the authors also identified. Three segments of the Drosophila MSL3 protein are highly conserved in MSL3L1, including 2 putative chromodomains, 1 at the N terminus and the other at the C terminus. Chromodomains, which form a characteristic tertiary structure and can interact with components of chromatin, have been implicated to play roles in chromatin organization and transcriptional regulation. MSL3L1 also contains a putative nuclear localization signal, a putative leucine zipper motif within the second chromodomain, and 2 potential tyrosine kinase phosphorylation sites. Prakash et al. (1999) identified human fetal kidney cDNAs representing an alternatively spliced MSL3L1 transcript that lacks exon 2. The predicted protein, which the authors referred to as isoform 2, is identical to the first isoform from amino acid 62 to the C terminus but does not contain the first 26 amino acids of the N-terminal chromodomain. Northern blot analysis detected a major 2.4-kb MSL3L1 transcript in all tissues examined, namely liver, pancreas, heart, lung, kidney, skeletal muscle, brain, and placenta, with highest expression in skeletal muscle and heart. A 2.6-kb transcript unique to skeletal muscle was also found. Northern blot analysis of E7, E11, E15, and E17 mouse embryos detected approximately equal levels of Msl311 expression in all embryos. The MSL3L1 gene spans 17 kb and contains 13 exons. It is transcribed from telomere to centromere. Prakash et al. (1999) showed that the MSL3L1 gene undergoes X inactivation.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   rakash, S. K.; Van den Veyver, I. B.; Franco, B.; Volta, M.;     Ballabio, A.; Zoghbi, H. Y.: Characterization of a novel chromo     domain gene in Xp22.3 with homology to Drosophila msl-3. Genomics     59: 77-84, 1999.

Further studies establishing the function and utilities of MSL3L1 are found in John Hopkins OMIM database record ID 604880, and in references numbered 85 listed hereinbelow.

Reference is now made to MSL3L1 BINDING SITE. male-specific lethal-3 (Drosophila)-like 1 (MSL3L1) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. MSL3L1 BINDING SITE is a host binding site found in the 3′ untranslated region of MSL3L1, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of MSL3L1 BINDING SITE, designated SEQ ID:83, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID: 80.

A further function of VGAM20 is therefore inhibition of male-specific lethal-3 (Drosophila)-like 1 (MSL3L1), a host gene which encodes a Protein that is essential for elevating transcription of the single x chromosome in the male., as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of MSL3L1 has been established by previous studies. The Drosophila male-specific lethal (msl) genes regulate transcription from the male X chromosome in a dosage compensation pathway that equalizes X-linked gene expression in males and females. The members of this gene family, including msl1, msl2, msl3, mle, and mof, encode proteins with no sequence similarity to known proteins. However, mutations in each of these genes produce a similar phenotype: sex-specific lethality of male embryos caused by the failure of mutants to increase transcription from the single male X chromosome. The MSL gene products assemble into a multiprotein transcriptional activation complex at hundreds of sites along the chromatin of the X chromosome. By searching sequence databases with the sequence of a BAC clone that maps to Xp22.3, Prakash et al. (1999) identified a human homolog of Drosophila msl3, MSL3-like-1 (MSL3L1). They isolated a cDNA containing a complete MSL3L1 coding sequence. The deduced 521-amino acid MSL3L1 protein shares 30% overall sequence identity with Drosophila MSL3 and 86% identity with mouse Msl311, which the authors also identified. Three segments of the Drosophila MSL3 protein are highly conserved in MSL3L1, including 2 putative chromodomains, 1 at the N terminus and the other at the C terminus. Chromodomains, which form a characteristic tertiary structure and can interact with components of chromatin, have been implicated to play roles in chromatin organization and transcriptional regulation. MSL3L1 also contains a putative nuclear localization signal, a putative leucine zipper motif within the second chromodomain, and 2 potential tyrosine kinase phosphorylation sites. Prakash et al. (1999) identified human fetal kidney cDNAs representing an alternatively spliced MSL3L1 transcript that lacks exon 2. The predicted protein, which the authors referred to as isoform 2, is identical to the first isoform from amino acid 62 to the C terminus but does not contain the first 26 amino acids of the N-terminal chromodomain. Northern blot analysis detected a major 2.4-kb MSL3L1 transcript in all tissues examined, namely liver, pancreas, heart, lung, kidney, skeletal muscle, brain, and placenta, with highest expression in skeletal muscle and heart. A 2.6-kb transcript unique to skeletal muscle was also found. Northern blot analysis of E7, E11, E15, and E17 mouse embryos detected approximately equal levels of Msl311 expression in all embryos. The MSL3L1 gene spans 17 kb and contains 13 exons. It is transcribed from telomere to centromere. Prakash et al. (1999) showed that the MSL3L1 gene undergoes X inactivation.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   rakash, S. K.; Van den Veyver, I. B.; Franco, B.; Volta, M.;     Ballabio, A.; Zoghbi, H. Y.: Characterization of a novel chromo     domain gene in Xp22.3 with homology to Drosophila msl-3. Genomics     59: 77-84, 1999.

Further studies establishing the function and utilities of MSL3L1 are found in John Hopkins OMIM database record ID 604880, and in references numbered 85 listed hereinbelow.

Reference is now made to MSL3L1 BINDING SITE. male-specific lethal-3 (Drosophila)-like 1 (MSL3L1) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. MSL3L1 BINDING SITE is a host binding site found in the 3′ untranslated region of MSL3L1, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of MSL3L1 BINDING SITE, designated SEQ ID:83, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID: 80.

Yet a further function of VGAM20 is therefore inhibition of male-specific lethal-3 (Drosophila)-like 1 (MSL3L1), a host gene which encodes a Protein that is essential for elevating transcription of the single x chromosome in the male., as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of MSL3L1 has been established by previous studies. The Drosophila male-specific lethal (msl) genes regulate transcription from the male X chromosome in a dosage compensation pathway that equalizes X-linked gene expression in males and females. The members of this gene family, including msl1, msl2, msl3, mle, and mof, encode proteins with no sequence similarity to known proteins. However, mutations in each of these genes produce a similar phenotype: sex-specific lethality of male embryos caused by the failure of mutants to increase transcription from the single male X chromosome. The MSL gene products assemble into a multiprotein transcriptional activation complex at hundreds of sites along the chromatin of the X chromosome. By searching sequence databases with the sequence of a BAC clone that maps to Xp22.3, Prakash et al. (1999) identified a human homolog of Drosophila msl3, MSL3-like-1 (MSL3L1). They isolated a cDNA containing a complete MSL3L1 coding sequence. The deduced 521-amino acid MSL3L1 protein shares 30% overall sequence identity with Drosophila MSL3 and 86% identity with mouse Msl311, which the authors also identified. Three segments of the Drosophila MSL3 protein are highly conserved in MSL3L1, including 2 putative chromodomains, 1 at the N terminus and the other at the C terminus. Chromodomains, which form a characteristic tertiary structure and can interact with components of chromatin, have been implicated to play roles in chromatin organization and transcriptional regulation. MSL3L1 also contains a putative nuclear localization signal, a putative leucine zipper motif within the second chromodomain, and 2 potential tyrosine kinase phosphorylation sites. Prakash et al. (1999) identified human fetal kidney cDNAs representing an alternatively spliced MSL3L1 transcript that lacks exon 2. The predicted protein, which the authors referred to as isoform 2, is identical to the first isoform from amino acid 62 to the C terminus but does not contain the first 26 amino acids of the N-terminal chromodomain. Northern blot analysis detected a major 2.4-kb MSL3L1 transcript in all tissues examined, namely liver, pancreas, heart, lung, kidney, skeletal muscle, brain, and placenta, with highest expression in skeletal muscle and heart. A 2.6-kb transcript unique to skeletal muscle was also found. Northern blot analysis of E7, E11, E15, and E17 mouse embryos detected approximately equal levels of Msl311 expression in all embryos. The MSL3L1 gene spans 17 kb and contains 13 exons. It is transcribed from telomere to centromere. Prakash et al. (1999) showed that the MSL3L1 gene undergoes X inactivation.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   rakash, S. K.; Van den Veyver, I. B.; Franco, B.; Volta, M.;     Ballabio, A.; Zoghbi, H. Y.: Characterization of a novel chromo     domain gene in Xp22.3 with homology to Drosophila msl-3. Genomics     59: 77-84, 1999.

Further studies establishing the function and utilities of MSL3L1 are found in John Hopkins OMIM database record ID 604880, and in references numbered 85 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1. The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to RAD51C BINDING SITE. RAD51 (S. cerevisiae) homolog C (RAD51C) is a host target gene of VGAM20, corresponding to VGAM20-HOST-TARGET GENE of FIG. 20A. RAD51C BINDING SITE is a host binding site found in the 3′ untranslated region of RAD51C, corresponding to HOST BINDING SITE of FIG. 20A. FIG. 20D illustrates the complementarity of the nucleotide sequence of RAD51C BINDING SITE, designated SEQ ID:84, to the nucleotide sequence of VGAM20 RNA of FIG. 20A, designated SEQ ID:80.

Yet another function of VGAM20 is therefore inhibition of RAD51 (S. cerevisiae) homolog C (RAD51C), a host gene which encodes a Protein that is a member of the RAD51 family of strand-transfer proteins, as part of a novel viral mechanism used by Alcelaphine herpesvirus 1 for attacking a host. Accordingly, utilities of VGAM20 include diagnosis, prevention and treatment of viral infection by Alcelaphine herpesvirus 1.

The function of RAD51C has been established by previous studies. The RAD51 family of related genes, identified in both yeast and humans, encode strand-transfer proteins thought to be involved in recombinational repair of DNA damage and in meiotic recombination. Several members of the mammalian RAD51 gene family have been identified; see, for example, RAD51A (179617), RAD51B (602948), XRCC3 (600675), and DMC1 (602721). Dosanjh et al. (1998) isolated and characterized a novel member of the RAD51 family, which they designated RAD51C. The authors identified several clones with amino acid similarity to the human XRCC3 and yeast Rad51 proteins by screening an EST database. They then isolated a full-length RAD51C cDNA from a human leukocyte cDNA library. The RAD51C cDNA encodes a predicted 376-amino acid protein that has 18 to 26% amino acid identity with other members of the human RAD51 family. By Northern blot analysis, Dosanjh et al. (1998) showed that RAD51C is expressed as an approximately 1.3-kb mRNA in a variety of human tissues, with highest expression in testis, heart muscle, spleen and prostate. Using a yeast 2-hybrid system, they demonstrated that the RAD51C protein interacts strongly with RAD51B and moderately with XRCC3, but not with itself.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   osanjh, M. K.; Collins, D. W.; Fan, W.; Lennon, G. G.; Albala, J.     S.; Shen, Z.; Schild, D.: Isolation and characterization of RAD51C,     a new human member of the RAD51 family of related genes. Nucleic     Acids Res. 26: 1179-1184, 1998. PubMed ID: 9469824 2. Masson, J.-Y.;     Stasiak, A. Z.; Stasiak, A.; Benson, F. E.; West, S. C.: Complex     formation by the human RAD51C and XRCC3 recombination repair     proteins. Proc. Nat. Acad. Sci. 98: 8440-8446, 2001.

Further studies establishing the function and utilities of RAD51C are found in John Hopkins OMIM database record ID 602774, and in references numbered 86-87 listed hereinbelow.

Reference is now made to FIG. 21A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 21 (VGAM21) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM21 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM21 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM21 GENE is a viral gene contained in the genome of Porcine adenovirus A. VGAM21-HOST TARGET GENE is a human gene contained in the human genome.

VGAM21 GENE encodes a VGAM21 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM21, VGAM21 PRECURSOR RNA, does not encoded a protein.

VGAM21 PRECURSOR RNA folds onto itself, forming VGAM21 FOLDED PRECURSOR RNA. As FIG. 21 illustrates, VGAM21 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM21 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM21 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM21-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM21-HOST-TARGET RNA. VGAM21-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM21 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM21-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM21 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 21A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM21 RNA to HOST BINDING SITE inhibits translation of VGAM21-HOST-TARGET RNA into VGAM21-HOST-TARGET PROTEIN. VGAM21-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM21-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM21. The mRNA of each of this plurality of host target genes of VGAM21 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM21 RNA, and which when bound by VGAM21 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM21. The plurality of host target genes of VGAM21 and their respective host binding sites, are described hereinbelow with reference to FIG. 21D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 21A with specific reference to translational inhibition exerted by VGAM21 on one or more host target genes of VGAM21, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM21 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

Reference is now made to FIG. 21B which shows the nucleotide sequence of VGAM21 PRECURSOR RNA of FIG. 21A, designated SEQ ID:95, and a probable nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96. The nucleotide sequence of SEQ ID:96, which is highly likely (over 75%) to be identical or highly similar to that of VGAM21, is marked by an underline within the sequence of VGAM21 PRECURSOR RNA.

Reference is now made to FIG. 21C, which shows the secondary folding of VGAM21 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM21 FOLDED PRECURSOR RNA, both of FIG. 21A. A probable (>75%) nucleotide sequence of VGAM21 RNA, designated SEQ ID:96 of FIG. 21B, is marked by an underline on VGAM21 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 21D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM21, each binding site corresponding to HOST BINDING SITE of FIG. 21A, and their complementarity to SEQ ID:96, which is highly likely (>75%) to be identical or highly similar to the nucleotide sequence of VGAM21 RNA of FIG. 21A.

As mentioned hereinabove with reference to FIG. 21A a function of VGAM21 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A. It is appreciated that specific functions, and accordingly utilities, of VGAM21 correlate with, and may be deduced from, the identity of the host target genes which VGAM21 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to ACTA1 BINDING SITE. actin, alpha 1, skeletal muscle (ACTA1) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. ACTA1 BINDING SITE is a host binding site found in the 5′ untranslated region of ACTA1, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of ACTA1 BINDING SITE, designated SEQ ID:97, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

A function of VGAM21 is therefore inhibition of actin, alpha 1, skeletal muscle (ACTA1), a host gene which encodes a Protein that is associated with muscle diseases: congenital myopathy with excess of thin myofilaments, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of ACTA1 has been established by previous studies. By use of a cDNA probe in somatic cell hybrids, Hanauer et al. (1984) assigned the gene for the alpha chain of skeletal muscle actin to chromosome 1. Actin sequences were found at high stringency also at 2p23-qter and 3pter-q21. Under conditions of low or medium stringency, actin sequences were demonstrated on the X (p11-p12) and Y chromosomes. Using a cDNA copy of the 3-prime untranslated region of the human skeletal alpha actin gene, Shows et al. (1984) mapped the gene to 1p12-1qter. This gene and that for cardiac alpha-actin (102540) are coexpressed in both human skeletal muscle and heart. Coexpression is not a function of linkage; the loci are on separate chromosomes: 1p21-qter and 15q11-qter, respectively (Gunning et al., 1984). Akkari et al. (1994) narrowed the assignment of the ACTA1 gene to 1q42 by fluorescence in situ hybridization. Also by fluorescence in situ hybridization, Ueyama et al. (1995) mapped the gene to 1q42.1. Using a panel of somatic cell hybrids, Alonso et al. (1993) confirmed the localization of the ACTA1 gene on human chromosome 1. On the basis of analysis of mouse/hamster somatic cell hybrids segregating mouse chromosomes, Czosnek et al. (1982) concluded that the skeletal actin gene is located on mouse chromosome 3. However, Alonso et al. (1993) found by PCR analysis of a microsatellite in an interspecific backcross that the gene, symbolized Actsk-1, is closely linked to tyrosine aminotransferase and adenine phosphoribosyltransferase on mouse chromosome 8. The Actsk-1 gene is situated between Tat and Aprt; the human homologs TAT (276600) and APRT (102600) are on human chromosome 16. Abonia et al. (1993) likewise mapped the Actsk-1 gene to mouse chromosome 8 by segregation of RFLVs in 2 interspecific backcross sets and in 4 recombinant inbred (RI) mouse sets. Nowak et al. (1999) reported mutations in the human skeletal muscle alpha-actin gene in association with 2 different muscle diseases: congenital myopathy with excess of thin myofilaments, also known as actin myopathy (Goebel et al., 1997), and nemaline myopathy (see 161800 and 256030). Both diseases are characterized by structural abnormalities of muscle fibers and variable degrees of muscle weakness. Nowak et al. (1999) identified 15 different missense mutations resulting in 14 different amino acid changes.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   bonia, J. P.; Abel, K. J.; Eddy, R. L.; Elliott, R. W.; Chapman, V.     M.; Shows, T. B.; Gross, K. W.: Linkage of Agt and Actsk-1 to distal     mouse chromosome 8 loci: a new conserved linkage. Mammalian Genome     4: 25-32, 1993. PubMed ID: 8093670 10. Nowak, K. J.;     Wattanasirichaigoon, D.; Goebel, H. H.; Wilce, M.; Pelin, K.;     Donner, K.; Jacob, R. L.; Hubner, C.; Oexle, K.; Anderson, J. R.;     Verity, C. M.; North, K. N.; and 13 others: Mutations in the     skeletal muscle alpha-actin gene in patients with actin myopathy and     nemaline myopathy. Nature Genet. 23: 208-212, 1999.

Further studies establishing the function and utilities of ACTA1 are found in John Hopkins OMIM database record ID 102610, and in references numbered 88-99 listed hereinbelow.

Reference is now made to EXTL1 BINDING SITE. exostoses (multiple)-like 1 (EXTL1) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. EXTL1 BINDING SITE is a host binding site found in the 5′ untranslated region of EXTL1, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of EXTL1 BINDING SITE, designated SEQ ID:98, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet another function of VGAM21 is therefore inhibition of exostoses (multiple)-like 1 (EXTL1), a host gene which encodes a Protein that probably contribute to the synthesis of heparan sulfate and heparin., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of EXTL1 has been established by previous studies. The tumor suppressors EXT1 (133700) and EXT2 (133701) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, termed EXTL by them, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different. Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin. Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none. Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses. By radiation hybrid analysis and by fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ise, C. A.; Clines, G. A.; Massa, H.; Trask, B. J.; Lovett, M.:     Identification and localization of the gene for EXTL, a third member     of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997.     PubMed ID: 9037597 2. Kim, B.-T.; Kitagawa, H.; Tamura, J.; Saito,     T.; Kusche-Gullberg, M.; Lindahl, U.; Sugahara, K.: Human tumor     suppressor EXT gene family members EXTL1 and EXTL3 encode     alpha-1,4-N-acetylgluco saminyltransferases that likely are involved     in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98:     7176-7181, 2001.

Further studies establishing the function and utilities of EXTL1 are found in John Hopkins OMIM database record ID 601738, and in references numbered 16-19 listed hereinbelow.

Reference is now made to FMNL BINDING SITE. formin-like (FMNL) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. FMNL BINDING SITE is a host binding site found in the 3′ untranslated region of FMNL, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of FMNL BINDING SITE, designated SEQ ID:99, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

An additional function of VGAM21 is therefore inhibition of formin-like (FMNL), a host gene which encodes a Protein that controls the reorganization of the actin cytoskeleton in association with Rac, as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of FMNL has been established by previous studies. By sequencing a recombinant cosmid library, Aronsson et al. (1998) identified 2 genes, NIK (604655) and C17ORF1B. Northern blot analysis revealed that C17ORF1B is expressed as a 1.8-kb transcript in heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. By directed sequencing of the cosmid library, Aronsson et al. (1998) showed that C17ORF1B contains 11 exons spanning 5.1 kb of genomic DNA. Yayoshi-Yamamoto et al. (2000) isolated cDNAs encoding mouse Frl-alpha and Frl-beta (formin-related gene in leukocytes) that appeared to be homologs of C17ORF1B. Western blot, immunofluorescence, and Northern blot analyses showed that Frl is expressed as a 160-kD cytosolic protein that is highly expressed in spleen, lymph node, and bone marrow cells and that it associates with Rac (see 602048) and profilin (see 176610). Yayoshi-Yamamoto et al. (2000) suggested that Frl may play a role in the control of reorganization of the actin cytoskeleton in association with Rac and in the regulation of the signal for cell survival. By FISH and radiation hybrid analysis, Aronsson et al. (1998) mapped the C17ORF1B gene to chromosome 17q21. Using exon-intron maps and mutation screening, Aronsson et al. (1998) found no disease-specific alterations in the C17ORF1B gene in a pedigree with frontotemporal dementia and parkinsonism linked to chromosome 17 (600274).

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ronsson, F. C.; Magnusson, P.; Andersson, B.; Karsten, S. L.;     Shibasaki, Y.; Lendon, C. L.; Goate, A. M.; Brookes, A. J.: The NIK     protein kinase and C17orf1 genes: chromosomal mapping, gene     structures and mutational screening in frontotemporal dementia and     parkinsonism linked to chromosome 17. Hum. Genet. 103:     340-345, 1998. PubMed ID: 9799091 2. Yayoshi-Yamamoto, S.; Taniuchi,     I.; Watanabe, T.: FRL, a novel formin-related protein, binds to Rac     and regulates cell motility and survival of macrophages. Molec.     Cell. Biol. 20: 6872-6881, 2000.

Further studies establishing the function and utilities of FMNL are found in John Hopkins OMIM database record ID 604656, and in references numbered 100-101 listed hereinbelow.

Reference is now made to PHKA2 BINDING SITE. phosphorylase kinase, alpha 2 (liver) (PHKA2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PHKA2 BINDING SITE is a host binding site found in the 5′ untranslated region of PHKA2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PHKA2 BINDING SITE, designated SEQ ID:100, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

A further function of VGAM21 is therefore inhibition of phosphorylase kinase, alpha 2 (liver) (PHKA2), a host gene which encodes a Enzyme that is associated with LIVER GLYCOGENOSIS, X-LINKED, TYPE I (glycogen storage disease viii), as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PHKA2 has been established by previous studies. Deficiency of liver phosphorylase kinase (PHK; ATP:phosphotransferase; EC 2.7.1.38) produces one of the mildest of the glycogenoses of man. The clinical symptoms include hepatomegaly, growth retardation, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis (Schimke et al., 1973; Willems et al., 1990). With age, these clinical and biochemical abnormalities gradually disappear and most adult patients are asymptomatic (Willems et al., 1990). Nagai et al. (1988) described renal tubular acidosis in a 2.5-year-old Japanese boy with phosphorylase kinase deficiency X-linked phosphorylase b kinase deficiency is similar to glycogen storage disease VI in that both have low phosphorylase activity in the absence of adenosine monophosphate (AMP); it differs in that phosphorylase kinase activity is low (Huijing, 1967). Williams and Field (1961) found low leukocyte phosphorylase activity in 2 affected brothers and normal activity in an unaffected brother and in the father. An intermediately low level in the mother, together with affected males, suggested X-linked inheritance. Wallis et al. (1966) restudied the family and with new methods found support for X-linkage. Huijing and Fernandez (1969) studied 2 kindreds, one of which had 6 affected plus 2 possibly affected males. The other had 20 affected males, 2 affected females, and 7 probably affected males. Huijing and Fernandez (1970) suggested that the affected females studied by Hug et al. (1969) were heterozygotes. Since phosphorylase kinase is known to be enzymatically activated (Krebs et al., 1964), it is possible that an activating enzyme is controlled by the X chromosome. By cloning cells of heterozygotes, Migeon and Huijing (1974) demonstrated some fibroblasts with enzymatic levels like those of affected hemizygotes. This was presented as proof of X-linkage and X-inactivation of the phosphorylase kinase locus. An X-linked codominant electrophoretic polymorphism of phosphorylase kinase is known in the mouse (Lyon et al., 1967). Huijing (1970) pointed out similarities and differences of the human and murine defects. Malthus et al. (1980) described deficiency of liver phosphorylase kinase in rats and concluded that it is autosomal recessive. This may not be a true exception to Ohno's law of the evolutionary conservatism of the X chromosome; see comment of Hug (1974) above. Schneider et al. (1993) reviewed the animal mutants that result in PHK-linked glycogenoses. Two different X-linked disorders are known, as well as an autosomal recessive PHK deficiency affecting the liver and most other tissues but not muscle, in the rat

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Willems, P. J.; Gerver, W. J. M.; Berger, R.; Fernandes, J.: The     natural history of liver glycogenosis due to phosphorylase kinase     deficiency: a longitudinal study of 41 patients. Europ. J. Pediat.     149: 268-271, 1990. PubMed ID: 2303074 Schneider, A.; Davidson, J.     J.; Wullrich, A.; Kilimann, M. W.: Phosphorylase kinase deficiency     in I-strain mice is associated with a frameshift mutation in the     alpha-subunit muscle isoform. Nature Genet. 5: 381-385, 1993.

Further studies establishing the function and utilities of PHKA2 are found in John Hopkins OMIM database record ID 306000, and in references numbered 102-143 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to PTK2 BINDING SITE. PTK2 protein tyrosine kinase 2 (PTK2) is a host target gene of VGAM21, corresponding to VGAM21-HOST-TARGET GENE of FIG. 21A. PTK2 BINDING SITE is a host binding site found in the 3′ untranslated region of PTK2, corresponding to HOST BINDING SITE of FIG. 21A. FIG. 21D illustrates the complementarity of the nucleotide sequence of PTK2 BINDING SITE, designated SEQ ID:101, to the nucleotide sequence of VGAM21 RNA of FIG. 21A, designated SEQ ID:96.

Yet a further function of VGAM21 is therefore inhibition of PTK2 protein tyrosine kinase 2 (PTK2), a host gene which encodes a Enzyme that involves in intracellular signal transduction pathway and is a putative homolog of chicken focal adhesion associated kinase., as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM21 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of PTK2 has been established by previous studies. Andre and Becker-Andre (1993) described focal adhesion kinase, also known as cytoplasmic protein-tyrosine kinase (PTK2), which lacks any significant homology with other kinases. See also 601212. It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts. A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix. Andre and Becker-Andre (1993) cloned a cDNA for human PTK2 using PCR methods. They detected expression of PTK2 in all organs tested, with the highest levels in brain and the lowest levels in heart and skeletal muscle. Andre and Becker-Andre (1993) detected an additional transcript in the brain encoding an N-terminally truncated form of the protein.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ndre, E.; Becker-Andre, M.: Expression of an N-terminally truncated     form of human focal adhesion kinase in brain. Biochem. Biophys. Res.     Commun. 190: 140-147, 1993. PubMed ID: 8422239 2. Fiedorek, F. T.,     Jr.; Kay, E. S.: Mapping of the focal adhesion kinase (Fadk) gene to     mouse chromosome 15 and human chromosome 8. Mammalian Genome 6:     123-126, 1995.

Further studies establishing the function and utilities of PTK2 are found in John Hopkins OMIM database record ID 600758, and in references numbered 144-147 listed hereinbelow.

Reference is now made to FIG. 22A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 22 (VGAM22) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM22 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM22 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM22 GENE is a viral gene contained in the genome of Porcine adenovirus A. VGAM22-HOST TARGET GENE is a human gene contained in the human genome.

VGAM22 GENE encodes a VGAM22 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM22, VGAM22 PRECURSOR RNA, does not encoded a protein.

VGAM22 PRECURSOR RNA folds onto itself, forming VGAM22 FOLDED PRECURSOR RNA. As FIG. 22 illustrates, VGAM22 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM22 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM22 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM22-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM22-HOST-TARGET RNA. VGAM22-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM22 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM22-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM22 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 22A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM22 RNA to HOST BINDING SITE inhibits translation of VGAM22-HOST-TARGET RNA into VGAM22-HOST-TARGET PROTEIN. VGAM22-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM22-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM22. The mRNA of each of this plurality of host target genes of VGAM22 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM22 RNA, and which when bound by VGAM22 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM22. The plurality of host target genes of VGAM22 and their respective host binding sites, are described hereinbelow with reference to FIG. 22D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 22A with specific reference to translational inhibition exerted by VGAM22 on one or more host target genes of VGAM22, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM22 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

Reference is now made to FIG. 22B which shows the nucleotide sequence of VGAM22 PRECURSOR RNA of FIG. 22A, designated SEQ ID:113, and a probable nucleotide sequence of VGAM22 RNA of FIG. 22A, designated SEQ ID:114. The nucleotide sequence of SEQ ID:114, which is highly likely (over 28%) to be identical or highly similar to that of VGAM22, is marked by an underline within the sequence of VGAM22 PRECURSOR RNA.

Reference is now made to FIG. 22C, which shows the secondary folding of VGAM22 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM22 FOLDED PRECURSOR RNA, both of FIG. 22A. A probable (>28%) nucleotide sequence of VGAM22 RNA, designated SEQ ID:114 of FIG. 22B, is marked by an underline on VGAM22 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 22D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM22, each binding site corresponding to HOST BINDING SITE of FIG. 22A, and their complementarity to SEQ ID:114, which is highly likely (>28%) to be identical or highly similar to the nucleotide sequence of VGAM22 RNA of FIG. 22A.

As mentioned hereinabove with reference to FIG. 22A a function of VGAM22 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A. It is appreciated that specific functions, and accordingly utilities, of VGAM22 correlate with, and may be deduced from, the identity of the host target genes which VGAM22 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to MAP3K14 BINDING SITE. mitogen-activated protein kinase kinase kinase 14 (MAP3K14) is a host target gene of VGAM22, corresponding to VGAM22-HOST TARGET GENE of FIG. 22A. MAP3K14 BINDING SITE is a host binding site found in the 3′ untranslated region of MAP3K14, corresponding to HOST BINDING SITE of FIG. 22A. FIG. 22D illustrates the complementarity of the nucleotide sequence of MAP3K14 BINDING SITE, designated SEQ ID:115, to the nucleotide sequence of VGAM22 RNA of FIG. 22A, designated SEQ ID:114.

a function of VGAM22 is therefore inhibition of mitogen-activated protein kinase kinase kinase 14 (MAP3K14), a host gene which encodes a Enzyme that is involved in the activation of nf-kappa-b and its transcriptional activity. induces the processing of nf-kappa-b 2/p100. could act in a receptor-selective manner (by similarity), as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of MAP3K14 has been established by previous studies. By functional analysis of NIK and a kinase-deficient NIK expressed in primary human cells and in inflamed rheumatoid arthritis tissue, Smith et al. (2001) showed that NIK has a selective role in signaling by the lymphotoxin-beta receptor (LTBR; 600979). They determined that NIK is not required for signaling in response to lipopolysaccharide, IL1, and TNFA and is not a generic IKK kinase

Animal model experiments lend further support to the function of MAP3K14. The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes and Peyer patches and disorganized splenic and thymic structures with immunodeficiency. Shinkura et al. (1999) cloned the mouse Nik gene and determined that a G-to-A transition leads to a gly855-to-arg substitution in the C terminus of the protein, causing alymphoplasia in aly/aly mice

It is appreciated that the abovementioned animal model for MAP3K14 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Shinkura, R.; Kitada, K.; Matsuda, F.; Tashiro, K.; Ikuta, K.;     Suzuki, M.; Kogishi, K.; Serikawa, T.; Honjo, T.: Alymphoplasia is     caused by a point mutation in the mouse gene encoding     Nf-kappa-b-inducing kinase. Nature Genet. 22: 74-77, 1999. PubMed     ID: 10319865. Smith, C.; Andreakos, E.; Crawley, J. B.; Brennan, F.     M.; Feldmann, M.; Foxwell, B. M. J.: NF-kappa-B-inducing kinase is     dispensable for activation of NF-kappa-B in inflammatory settings     but essential for lymphotoxin beta receptor activation of NF-kappa-B     in primary human fibroblasts. J. Immun. 167: 5895-5903, 2001.

Further studies establishing the function and utilities of MAP3K14 are found in John Hopkins OMIM database record ID 604655, and in references numbered 148-154 listed hereinbelow.

Reference is now made to MAP3K14 BINDING SITE. mitogen-activated protein kinase kinase kinase 14 (MAP3K14) is a host target gene of VGAM22, corresponding to VGAM22-HOST TARGET GENE of FIG. 22A. MAP3K14 BINDING SITE is a host binding site found in the 3′ untranslated region of MAP3K14, corresponding to HOST BINDING SITE of FIG. 22A. FIG. 22D illustrates the complementarity of the nucleotide sequence of MAP3K14 BINDING SITE, designated SEQ ID:115, to the nucleotide sequence of VGAM22 RNA of FIG. 22A, designated SEQ ID:114.

a function of VGAM22 is therefore inhibition of mitogen-activated protein kinase kinase kinase 14 (MAP3K14), a host gene which encodes a Enzyme that is involved in the activation of nf-kappa-b and its transcriptional activity. induces the processing of nf-kappa-b 2/p100. could act in a receptor-selective manner (by similarity), as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of MAP3K14 has been established by previous studies. By functional analysis of NIK and a kinase-deficient NIK expressed in primary human cells and in inflamed rheumatoid arthritis tissue, Smith et al. (2001) showed that NIK has a selective role in signaling by the lymphotoxin-beta receptor (LTBR; 600979). They determined that NIK is not required for signaling in response to lipopolysaccharide, ILL and TNFA and is not a generic IKK kinase

Animal model experiments lend further support to the function of MAP3K14. The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes and Peyer patches and disorganized splenic and thymic structures with immunodeficiency. Shinkura et al. (1999) cloned the mouse Nik gene and determined that a G-to-A transition leads to a gly855-to-arg substitution in the C terminus of the protein, causing alymphoplasia in aly/aly mice

It is appreciated that the abovementioned animal model for MAP3K14 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Shinkura, R.; Kitada, K.; Matsuda, F.; Tashiro, K.; Ikuta, K.;     Suzuki, M.; Kogishi, K.; Serikawa, T.; Honjo, T.: Alymphoplasia is     caused by a point mutation in the mouse gene encoding     Nf-kappa-b-inducing kinase. Nature Genet. 22: 74-77, 1999. PubMed     ID: 10319865. Smith, C.; Andreakos, E.; Crawley, J. B.; Brennan, F.     M.; Feldmann, M.; Foxwell, B. M. J.: NF-kappa-B-inducing kinase is     dispensable for activation of NF-kappa-B in inflammatory settings     but essential for lymphotoxin beta receptor activation of NF-kappa-B     in primary human fibroblasts. J. Immun. 167: 5895-5903, 2001.

Further studies establishing the function and utilities of MAP3K14 are found in John Hopkins OMIM database record ID 604655, and in references numbered 148-154 listed hereinbelow.

Reference is now made to MAP3K14 BINDING SITE. mitogen-activated protein kinase kinase kinase 14 (MAP3K14) is a host target gene of VGAM22, corresponding to VGAM22-HOST TARGET GENE of FIG. 22A. MAP3K14 BINDING SITE is a host binding site found in the 3′ untranslated region of MAP3K14, corresponding to HOST BINDING SITE of FIG. 22A. FIG. 22D illustrates the complementarity of the nucleotide sequence of MAP3K14 BINDING SITE, designated SEQ ID:115, to the nucleotide sequence of VGAM22 RNA of FIG. 22A, designated SEQ ID:114.

a function of VGAM22 is therefore inhibition of mitogen-activated protein kinase kinase kinase 14 (MAP3K14), a host gene which encodes a Enzyme that is involved in the activation of nf-kappa-b and its transcriptional activity. induces the processing of nf-kappa-b 2/p100. could act in a receptor-selective manner (by similarity), as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of MAP3K14 has been established by previous studies. By functional analysis of NIK and a kinase-deficient NIK expressed in primary human cells and in inflamed rheumatoid arthritis tissue, Smith et al. (2001) showed that NIK has a selective role in signaling by the lymphotoxin-beta receptor (LTBR; 600979). They determined that NIK is not required for signaling in response to lipopolysaccharide, ILL and TNFA and is not a generic IKK kinase

Animal model experiments lend further support to the function of MAP3K14. The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes and Peyer patches and disorganized splenic and thymic structures with immunodeficiency. Shinkura et al. (1999) cloned the mouse Nik gene and determined that a G-to-A transition leads to a gly855-to-arg substitution in the C terminus of the protein, causing alymphoplasia in aly/aly mice

It is appreciated that the abovementioned animal model for MAP3K14 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Shinkura, R.; Kitada, K.; Matsuda, F.; Tashiro, K.; Ikuta, K.;     Suzuki, M.; Kogishi, K.; Serikawa, T.; Honjo, T.: Alymphoplasia is     caused by a point mutation in the mouse gene encoding     Nf-kappa-b-inducing kinase. Nature Genet. 22: 74-77, 1999. PubMed     ID: 10319865. Smith, C.; Andreakos, E.; Crawley, J. B.; Brennan, F.     M.; Feldmann, M.; Foxwell, B. M. J.: NF-kappa-B-inducing kinase is     dispensable for activation of NF-kappa-B in inflammatory settings     but essential for lymphotoxin beta receptor activation of NF-kappa-B     in primary human fibroblasts. J. Immun. 167: 5895-5903, 2001.

Further studies establishing the function and utilities of MAP3K14 are found in John Hopkins OMIM database record ID 604655, and in references numbered 148-154 listed hereinbelow.

Reference is now made to MAP3K14 BINDING SITE. mitogen-activated protein kinase kinase kinase 14 (MAP3K14) is a host target gene of VGAM22, corresponding to VGAM22-HOST TARGET GENE of FIG. 22A. MAP3K14 BINDING SITE is a host binding site found in the 3′ untranslated region of MAP3K14, corresponding to HOST BINDING SITE of FIG. 22A. FIG. 22D illustrates the complementarity of the nucleotide sequence of MAP3K14 BINDING SITE, designated SEQ ID:115, to the nucleotide sequence of VGAM22 RNA of FIG. 22A, designated SEQ ID:114.

a function of VGAM22 is therefore inhibition of mitogen-activated protein kinase kinase kinase 14 (MAP3K14), a host gene which encodes a Enzyme that is involved in the activation of nf-kappa-b and its transcriptional activity. induces the processing of nf-kappa-b 2/p100. could act in a receptor-selective manner (by similarity), as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of MAP3K14 has been established by previous studies. By functional analysis of NIK and a kinase-deficient NIK expressed in primary human cells and in inflamed rheumatoid arthritis tissue, Smith et al. (2001) showed that NIK has a selective role in signaling by the lymphotoxin-beta receptor (LTBR; 600979). They determined that NIK is not required for signaling in response to lipopolysaccharide, ILL and TNFA and is not a generic IKK kinase

Animal model experiments lend further support to the function of MAP3K14. The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes and Peyer patches and disorganized splenic and thymic structures with immunodeficiency. Shinkura et al. (1999) cloned the mouse Nik gene and determined that a G-to-A transition leads to a gly855-to-arg substitution in the C terminus of the protein, causing alymphoplasia in aly/aly mice

It is appreciated that the abovementioned animal model for MAP3K14 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Shinkura, R.; Kitada, K.; Matsuda, F.; Tashiro, K.; Ikuta, K.;     Suzuki, M.; Kogishi, K.; Serikawa, T.; Honjo, T.: Alymphoplasia is     caused by a point mutation in the mouse gene encoding     Nf-kappa-b-inducing kinase. Nature Genet. 22: 74-77, 1999. PubMed     ID: 10319865. Smith, C.; Andreakos, E.; Crawley, J. B.; Brennan, F.     M.; Feldmann, M.; Foxwell, B. M. J.: NF-kappa-B-inducing kinase is     dispensable for activation of NF-kappa-B in inflammatory settings     but essential for lymphotoxin beta receptor activation of NF-kappa-B     in primary human fibroblasts. J. Immun. 167: 5895-5903, 2001.

Further studies establishing the function and utilities of MAP3K14 are found in John Hopkins OMIM database record ID 604655, and in references numbered 148-154 listed hereinbelow.

Reference is now made to MAP3K14 BINDING SITE. mitogen-activated protein kinase kinase kinase 14 (MAP3K14) is a host target gene of VGAM22, corresponding to VGAM22-HOST TARGET GENE of FIG. 22A. MAP3K14 BINDING SITE is a host binding site found in the 3′ untranslated region of MAP3K14, corresponding to HOST BINDING SITE of FIG. 22A. FIG. 22D illustrates the complementarity of the nucleotide sequence of MAP3K14 BINDING SITE, designated SEQ ID:115, to the nucleotide sequence of VGAM22 RNA of FIG. 22A, designated SEQ ID:114.

a function of VGAM22 is therefore inhibition of mitogen-activated protein kinase kinase kinase 14 (MAP3K14), a host gene which encodes a Enzyme that is involved in the activation of nf-kappa-b and its transcriptional activity. induces the processing of nf-kappa-b 2/p100. could act in a receptor-selective manner (by similarity), as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of MAP3K14 has been established by previous studies. By functional analysis of NIK and a kinase-deficient NIK expressed in primary human cells and in inflamed rheumatoid arthritis tissue, Smith et al. (2001) showed that NIK has a selective role in signaling by the lymphotoxin-beta receptor (LTBR; 600979). They determined that NIK is not required for signaling in response to lipopolysaccharide, ILL and TNFA and is not a generic IKK kinase

Animal model experiments lend further support to the function of MAP3K14. The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes and Peyer patches and disorganized splenic and thymic structures with immunodeficiency. Shinkura et al. (1999) cloned the mouse Nik gene and determined that a G-to-A transition leads to a gly855-to-arg substitution in the C terminus of the protein, causing alymphoplasia in aly/aly mice

It is appreciated that the abovementioned animal model for MAP3K14 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Shinkura, R.; Kitada, K.; Matsuda, F.; Tashiro, K.; Ikuta, K.;     Suzuki, M.; Kogishi, K.; Serikawa, T.; Honjo, T.: Alymphoplasia is     caused by a point mutation in the mouse gene encoding     Nf-kappa-b-inducing kinase. Nature Genet. 22: 74-77, 1999. PubMed     ID: 10319865. Smith, C.; Andreakos, E.; Crawley, J. B.; Brennan, F.     M.; Feldmann, M.; Foxwell, B. M. J.: NF-kappa-B-inducing kinase is     dispensable for activation of NF-kappa-B in inflammatory settings     but essential for lymphotoxin beta receptor activation of NF-kappa-B     in primary human fibroblasts. J. Immun. 167: 5895-5903, 2001.

Further studies establishing the function and utilities of MAP3K14 are found in John Hopkins OMIM database record ID 604655, and in references numbered 148-154 listed hereinbelow.

Reference is now made to MAP3K14 BINDING SITE. mitogen-activated protein kinase kinase kinase 14 (MAP3K14) is a host target gene of VGAM22, corresponding to VGAM22-HOST TARGET GENE of FIG. 22A. MAP3K14 BINDING SITE is a host binding site found in the 3′ untranslated region of MAP3K14, corresponding to HOST BINDING SITE of FIG. 22A. FIG. 22D illustrates the complementarity of the nucleotide sequence of MAP3K14 BINDING SITE, designated SEQ ID:115, to the nucleotide sequence of VGAM22 RNA of FIG. 22A, designated SEQ ID:114.

a function of VGAM22 is therefore inhibition of mitogen-activated protein kinase kinase kinase 14 (MAP3K14), a host gene which encodes a Enzyme that is involved in the activation of nf-kappa-b and its transcriptional activity. induces the processing of nf-kappa-b 2/p100. could act in a receptor-selective manner (by similarity), as part of a novel viral mechanism used by Porcine adenovirus A for attacking a host. Accordingly, utilities of VGAM22 include diagnosis, prevention and treatment of viral infection by Porcine adenovirus A.

The function of MAP3K14 has been established by previous studies. By functional analysis of NIK and a kinase-deficient NIK expressed in primary human cells and in inflamed rheumatoid arthritis tissue, Smith et al. (2001) showed that NIK has a selective role in signaling by the lymphotoxin-beta receptor (LTBR; 600979). They determined that NIK is not required for signaling in response to lipopolysaccharide, ILL and TNFA and is not a generic IKK kinase

Animal model experiments lend further support to the function of MAP3K14. The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes and Peyer patches and disorganized splenic and thymic structures with immunodeficiency. Shinkura et al. (1999) cloned the mouse Nik gene and determined that a G-to-A transition leads to a gly855-to-arg substitution in the C terminus of the protein, causing alymphoplasia in aly/aly mice

It is appreciated that the abovementioned animal model for MAP3K14 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Shinkura, R.; Kitada, K.; Matsuda, F.; Tashiro, K.; Ikuta, K.;     Suzuki, M.; Kogishi, K.; Serikawa, T.; Honjo, T.: Alymphoplasia is     caused by a point mutation in the mouse gene encoding     Nf-kappa-b-inducing kinase. Nature Genet. 22: 74-77, 1999. PubMed     ID: 10319865. Smith, C.; Andreakos, E.; Crawley, J. B.; Brennan, F.     M.; Feldmann, M.; Foxwell, B. M. J.: NF-kappa-B-inducing kinase is     dispensable for activation of NF-kappa-B in inflammatory settings     but essential for lymphotoxin beta receptor activation of NF-kappa-B     in primary human fibroblasts. J. Immun. 167: 5895-5903, 2001.

Further studies establishing the function and utilities of MAP3K14 are found in John Hopkins OMIM database record ID 604655, and in references numbered 148-154 listed hereinbelow.

Reference is now made to FIG. 23A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 23 (VGAM23) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM23 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM23 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM23 GENE is a viral gene contained in the genome of Equine herpesvirus 2. VGAM23-HOST TARGET GENE is a human gene contained in the human genome.

VGAM23 GENE encodes a VGAM23 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM23, VGAM23 PRECURSOR RNA, does not encoded a protein.

VGAM23 PRECURSOR RNA folds onto itself, forming VGAM23 FOLDED PRECURSOR RNA. As FIG. 23 illustrates, VGAM23 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM23 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM23 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM23-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM23-HOST-TARGET RNA. VGAM23-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM23 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM23-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM23 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 23A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM23 RNA to HOST BINDING SITE inhibits translation of VGAM23-HOST-TARGET RNA into VGAM23-HOST-TARGET PROTEIN. VGAM23-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM23-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM23. The mRNA of each of this plurality of host target genes of VGAM23 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM23 RNA, and which when bound by VGAM23 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM23. The plurality of host target genes of VGAM23 and their respective host binding sites, are described hereinbelow with reference to FIG. 23D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 23A with specific reference to translational inhibition exerted by VGAM23 on one or more host target genes of VGAM23, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM23 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

Reference is now made to FIG. 23B which shows the nucleotide sequence of VGAM23 PRECURSOR RNA of FIG. 23A, designated SEQ ID:121, and a probable nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122. The nucleotide sequence of SEQ ID:122, which is highly likely (over 28%) to be identical or highly similar to that of VGAM23, is marked by an underline within the sequence of VGAM23 PRECURSOR RNA.

Reference is now made to FIG. 23C, which shows the secondary folding of VGAM23 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM23 FOLDED PRECURSOR RNA, both of FIG. 23A. A probable (>28%) nucleotide sequence of VGAM23 RNA, designated SEQ ID:122 of FIG. 23B, is marked by an underline on VGAM23 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 23D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM23, each binding site corresponding to HOST BINDING SITE of FIG. 23A, and their complementarity to SEQ ID:122, which is highly likely (>28%) to be identical or highly similar to the nucleotide sequence of VGAM23 RNA of FIG. 23A.

As mentioned hereinabove with reference to FIG. 23A a function of VGAM23 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2. It is appreciated that specific functions, and accordingly utilities, of VGAM23 correlate with, and may be deduced from, the identity of the host target genes which VGAM23 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to ATP11A BINDING SITE. ATPase, Class VI, type 11A (ATP11A) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. ATP11A BINDING SITE is a host binding site found in the 3′ untranslated region of ATP11A, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of ATP11A BINDING SITE, designated SEQ ID:123, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

a function of VGAM23 is therefore inhibition of ATPase, Class VI, type 11A (ATP11A), a host gene which encodes a Enzyme that is phosphorylated in their intermediate state, drives uphill transport of ions across membranes., as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of ATP11A has been established by previous studies. Kikuno et al. (1999) isolated a partial cDNA encoding ATP11A, which they called KIAA1021, from a brain cDNA library. Based on homology analysis, they predicted that the KIAA1021 protein is a probable calcium-transporting ATPase. RT-PCR analysis detected wide but moderate expression, with lowest levels in spleen, pancreas, testis, and most brain regions.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ikuno, R.; Nagase, T.; Ishikawa, K.; Hirosawa, M.; Miyajima, N.;     Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the     coding sequences of unidentified human genes. XIV. The complete     sequences of 100 new cDNA clones from brain which code for large     proteins in vitro. DNA Res. 6: 197-205, 1999.

Further studies establishing the function and utilities of ATP11A are found in John Hopkins OMIM database record ID 605868, and in references numbered 155-156 listed hereinbelow.

Reference is now made to BCL2L2 BINDING SITE. BCL2-like 2 (BCL2L2) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. BCL2L2 BINDING SITE is a host binding site found in the 3′ untranslated region of BCL2L2, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of BCL2L2 BINDING SITE, designated SEQ ID:124, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet another function of VGAM23 is therefore inhibition of BCL2-like 2 (BCL2L2), a host gene which encodes a Protein that promotes cell survival, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of BCL2L2 has been established by previous studies. Gibson et al. (1996) used degenerate PCR to clone a novel BCL2 homolog which they denoted BCLW. The gene encodes a 193-amino acid polypeptide. Gibson et al. (1996) also isolated the mouse BCLW gene; its amino acid sequence is 99% identical to that of the human gene. Mouse BCLW is expressed as a 3.7-kb mRNA in a variety of tissues, with highest expression in brain, colon, and salivary gland. In mouse hematopoietic cell lines, BCLW is expressed in myeloid cells and to a lesser extent in lymphoid cells. Like BCL2, expressed BCLW promotes cell survival under a variety of cytotoxic conditions. Gibson et al. (1996) used fluorescence in situ hybridization to map the BCLW gene to human chromosome 14q11.2-q12.

Animal model experiments lend further support to the function of BCL2L2. To identify genes required for mammalian spermatogenesis, Ross et al. (1998) screened lines of mutant mice created using a retroviral gene-trap system for male infertility. Homozygous ROSA41 male mice exhibited sterility associated with progressive testicular degeneration. Germ cell defects were first observed at 19 days postnatal. Spermatogenesis was blocked during late spermiogenesis in young adults. Gradual depletion of all stages of germ cells resulted in a Sertoli-cell-only phenotype by approximately 6 months of age. Subsequently, almost all Sertoli cells were lost from the seminiferous tubules, and the Leydig cell population was reduced. Molecular analysis indicated that the gene mutated in these mice is BCLW, a death-protecting member of the Bcl2 family. The mutant allele of Bclw in ROSA41 did not produce a Bclw polypeptide. Expression of Bclw in the testis appeared to be restricted to elongating spermatids and Sertoli cells.

It is appreciated that the abovementioned animal model for BCL2L2 is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   ibson, L.; Holmgreen, S. P.; Huang, D. C. S.; Bernard, O.;     Copeland, N. G.; Jenkins, N. A.; Sutherland, G. R.; Baker, E.;     Adams, J. M.; Cory, S.: bcl-w, a novel member of the bcl-2 family,     promotes cell survival. Oncogene 13: 665-675, 1996. PubMed ID:     8761287 2. Ross, A. J.; Waymire, K. G.; Moss, J. E.; Parlow, A. F.;     Skinner, M. K.; Russell, L. D.; MacGregor, G. R.: Testicular     degeneration in Bclw-deficient mice. Nature Genet. 18: 251-256,     1998.

Further studies establishing the function and utilities of BCL2L2 are found in John Hopkins OMIM database record ID 601931, and in references numbered 157-158 listed hereinbelow.

Reference is now made to CLNS1A BINDING SITE. chloride channel, nucleotide-sensitive, 1A (CLNS1A) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. CLNS1A BINDING SITE is a host binding site found in the 3′ untranslated region of CLNS1A, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of CLNS1A BINDING SITE, designated SEQ ID:125, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

An additional function of VGAM23 is therefore inhibition of chloride channel, nucleotide-sensitive, 1A (CLNS1A), a host gene which encodes a Protein that may participate in cellular volume control, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of CLNS1A has been established by previous studies. Anguita et al. (1995) cloned a novel gene encoding the chloride channel I(Cln) from a human ocular ciliary epithelial cell cDNA library. The gene encodes a 237-amino acid polypeptide that is over 90% identical to rat and canine I(Cln). The predicted protein contains 4 putative transmembrane domains. By Northern blot analysis, Nagl et al. (1996) found that the gene is expressed as an approximately 1.7-kb message in a variety of human tissues. Nagl et al. (1996) cloned the genomic DNA of the CLNS1A gene and showed that the gene comprises several exons spanning 19 kb of the genome. Schwartz et al. (1997) cloned I(Cln) from human reticulocyte cDNA. I(Cln) protein from red blood cell ghost membranes migrated as 2 bands, 37 and 43 kD, on SDS-PAGE. Schwartz et al. (1997) immunolocalized I(Cln) to the red blood cell membrane and, by the yeast 2-hybrid system, demonstrated that it formed stable complexes with beta-actin (102630). The authors suggested that I(Cln) is involved in chloride transport and volume regulation in red blood cells.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   nguita, J.; Chalfant, M. L.; Civan, M. M.; Coca-Prados, M.:     Molecular cloning of the human volume-sensitive chloride conductance     regulatory protein, pI(Cln), from ocular ciliary epithelium.     Biochem. Biophys. Res. Commun. 208: 89-95, 1995. PubMed ID:     7887970 2. Buyse, G.; De Greef, C.; Raeymaekers, L.; Droogmans, G.;     Nilius, B.; Eggermont, J.: The ubiquitously expressed pI(Cln)     protein forms homomeric complexes in vitro. Biochem. Biophys. Res.     Commun. 218: 822-827, 1996.

Further studies establishing the function and utilities of CLNS1A are found in John Hopkins OMIM database record ID 602158, and in references numbered 159-162 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

A further function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Another function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet another function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

An additional function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

A further function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Another function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet another function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

An additional function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

A further function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to DMD BINDING SITE. dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD) is a host target gene of VGAM23, corresponding to VGAM23-HOST TARGET GENE of FIG. 23A. DMD BINDING SITE is a host binding site found in the 3′ untranslated region of DMD, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of DMD BINDING SITE, designated SEQ ID:126, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Another function of VGAM23 is therefore inhibition of dystrophin (muscular dystrophy, Duchenne and Becker types), includes D (DMD), a host gene which encodes a Protein that is associated with duchenne muscular dystrophy (dmd) and becker muscular dystrophy, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of DMD has been established by previous studies. Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009. Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis. X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer 1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. The authors suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.

Animal model experiments lend further support to the function of DMD. Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

It is appreciated that the abovementioned animal model for DMD is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   De Angelis, F. G.; Sthandier, O.; Berarducci, B.; Toso, S.;     Galluzzi, G.; Ricci, E.; Cossu, G.; Bozzoni, I.: Chimeric snRNA     molecules carrying antisense sequences against the splice junctions     of exon 51 of the dystrophin pre-mRNA induce exon skipping and     restoration of a dystrophin synthesis in delta-48-50 DMD cells. Proc     Nat. Acad. Sci. 99: 9456-9461, 2002. PubMed ID: 12077324 14.     Bastianutto, C.; Bestard, J. A.; Lahnakoski, K.; Broere, D.; De     Visser, M.; Zaccolo, M.; Pozzan, T.; Ferlini, A.; Muntoni, F.;     Patarnello, T.; Klamut, H. J.: Dystrophin muscle enhancer 1 is     implicated in the activation of non-muscle isoforms in the skeletal     muscle of patients with X-linked dilated cardiomyopathy. Hum. Molec.     Genet. 10: 2627-2635, 2001.

Further studies establishing the function and utilities of DMD are found in John Hopkins OMIM database record ID 300377, and in references numbered 163-261 listed hereinbelow.

Reference is now made to KRT2A BINDING SITE. keratin 2A (epidermal ichthyosis bullosa of Siemens) (KRT2A) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. KRT2A BINDING SITE is a host binding site found in the 3′ untranslated region of KRT2A, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of KRT2A BINDING SITE, designated SEQ ID:127, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet another function of VGAM23 is therefore inhibition of keratin 2A (epidermal ichthyosis bullosa of Siemens) (KRT2A), a host gene which encodes a Protein that is associated with ICHTHYOSIS BULLOSA OF SIEMENS, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of KRT2A has been established by previous studies. Keratins are the major gene product of keratinocytes and form the intermediate filament cytoskeletal network in these cells. Intermediate filament proteins consist of a central alpha-helical rod domain flanked by nonhelical sequences of varying size and composition. Keratin proteins fall into 2 classes on the basis of their electrophoretic properties and sequence similarities. One member of each class is required to form the heterodimeric coiled-coil precursor which through both lateral and longitudinal associations form the mature keratin intermediate filament. The major epidermal keratins of the type I class are KRT9 (144200), KRT10 (148080), KRT14 (148066), and KRT16 (148067); the major epidermal keratins of the type II class are KRT1 (139350), KRT2E, KRT5 (148040), KRT6A (148041), and KRT6B (148042). The expression of individual keratins is specific both for body site and for stage of differentiation of the epidermal keratinocyte. Keratinocytes in the basal layer express KRT5 and KRT14. Upon differentiation and migration to the spinous layer, these genes are downregulated and the expression of KRT1 and KRT10 is induced. In cells of the upper spinous layer, KRT2E and KRT9 are expressed. Although the expression of KRT9 is limited to palmoplantar epidermis, KRT2E is expressed not only in this tissue but also in other regions, notably the epidermis covering the knee, thigh, and groin. It is not known whether these keratins simply replace their respective type I or type II counterpart in the preexisting KRT1/KRT10 network or dimerize with another, as yet undiscovered keratin partner. The other major epidermal keratins, KRT6 and KRT16, are normally expressed in the outer root sheath of the hair follicle and in palmoplantar epidermis Smith et al. (1998) determined the genomic organization and complete sequence of the KRT2E gene, which consists of 9 exons spanning 7,634 by of DNA. By high-resolution radiation hybrid mapping, they localized the gene to the interval between microsatellite markers D125368 and a specific CHLC marker. Several intragenic polymorphisms were detected, including an 18-bp duplication in exon 1, corresponding to the V1 domain of the K2e polypeptide. Two novel mutations, N192Y in the 1A domain and E482K in the 2B domain of K2e, were found in families with IBS

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   remer, H.; Zeeuwen, P.; McLean, W. H. I.; Mariman, E. C. M.;     Lane, E. B.; van de Kerkhof, P. C. M.; Ropers, H.-H.; Steijlen, P.     M.: Ichthyosis bullosa of Siemens is caused by mutations in the     keratin 2e gene. J. Invest. Derm. 103: 286-289, 1994. PubMed ID:     8077693 2. Collin, C.; Moll, R.; Kubicka, S.; Ouhayoun, J.-P.;     Franke, W. W.: Characterization of human cytokeratin 2, an epidermal     cytoskeletal protein synthesized late during differentiation. Exp.     Cell Res. 202: 132-141, 1992.

Further studies establishing the function and utilities of KRT2A are found in John Hopkins OMIM database record ID 600194, and in references numbered 262-269 listed hereinbelow.

Reference is now made to PAIP2 BINDING SITE. PABP-interacting protein 2 (PAIP2) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. PAIP2 BINDING SITE is a host binding site found in the 3′ untranslated region of PAIP2, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of PAIP2 BINDING SITE, designated SEQ ID:128, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

An additional function of VGAM23 is therefore inhibition of PABP-interacting protein 2 (PAIP2), a host gene which encodes a Protein that acts as a repressor of translation., as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of PAIP2 has been established by previous studies. By Far Western interaction cloning using human PABP as the probe and a placenta cDNA expression library, Khaleghpour et al. (2001) isolated a 1.4-kb cDNA encoding PAIP2. The highly acidic (predicted pI of 3.9), 127-amino acid protein has a predicted molecular mass of 14.5 kD and acts as a repressor of translation both in vitro and in vivo. PAIP2 preferentially inhibited translation of a poly(A)-containing mRNA but had no effect on the translation of hepatitis C virus mRNA, which is cap and eIF4G (see 600495) independent. The authors showed that PAIP2 decreases the affinity of PABP for poly(A) RNA and disrupts the repeating structure of poly(A) ribonucleoprotein. Furthermore, PAIP2 was found to compete with PAIP1 for PABP binding. Thus, Khaleghpour et al. (2001) concluded that PAIP2 inhibits translation by interdicting PABP function.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   haleghpour, K.; Svitkin, Y. V.; Craig, A. W.; DeMaria, C. T.;     Deo, R. C.; Burley, S. K.; Sonenberg, N.: Translational repression     by a novel partner of human poly(A) binding protein, Paip2. Molec.     Cell 7: 205-216, 2001.

Further studies establishing the function and utilities of PAIP2 are found in John Hopkins OMIM database record ID 605604, and in references numbered 270-271 listed hereinbelow.

Reference is now made to PREP BINDING SITE. prolyl endopeptidase (PREP) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. PREP BINDING SITE is a host binding site found in the 3′ untranslated region of PREP, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of PREP BINDING SITE, designated SEQ ID:129, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

A further function of VGAM23 is therefore inhibition of prolyl endopeptidase (PREP), a host gene which encodes a Enzyme that cleaves peptide bonds at the C-terminal side of proline residues., as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of PREP has been established by previous studies. Prolyl endopeptidase (EC 3.4.21.26) is a large cytosolic enzyme that belongs to a distinct class of serine peptidases. The enzyme is involved in the maturation and degradation of peptide hormones and neuropeptides. PREP cleaves peptide bonds at the C-terminal side of proline residues. Its activity is confined to action on oligopeptides of less than 10 kD and it has an absolute requirement for the trans-configuration of the peptide bond preceding proline. Vanhoof et al. (1994) sequenced the human cDNA encoding prolyl endopeptidase. A complete cDNA was 2,562 nucleotides long and contained an open reading frame coding for a protein of 710 amino acids. Comparison of the sequences from human lymphocyte PREP and that of pig brain showed 97% identity. Fulop et al. (1998) reported the 1.4-angstrom resolution crystal structure of the porcine PREP enzyme. The enzyme contains a peptidase domain with an alpha/beta hydrolase fold, and its catalytic triad (ser554, his680, asp641) is covered by the central tunnel of an unusual beta propeller. This domain makes PREP an oligopeptidase by excluding large structured peptides from the active site. In this way, the propeller protects larger peptides and proteins from proteolysis in the cytosol.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   anhoof, G.; Goossens, F.; Hendriks, L.; De Meester, I.; Hendriks,     D.; Vriend, G.; Van Broeckhoven, C.; Scharpe, S.: Cloning and     sequence analysis of the gene encoding human lymphocyte prolyl     endopeptidase. Gene 149: 363-366, 1994. PubMed ID: 7959018 1. Fulop,     V.; Bocskei, Z.; Polgar, L.: Prolyl oligopeptidase: an unusual     beta-propeller domain regulates proteolysis. Cell 94: 161-170, 1998.

Further studies establishing the function and utilities of PREP are found in John Hopkins OMIM database record ID 600400, and in references numbered 272-274 listed hereinbelow.

Reference is now made to WASF3 BINDING SITE. WAS protein family, member 3 (WASF3) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. WASF3 BINDING SITE is a host binding site found in the 3′ untranslated region of WASF3, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of WASF3 BINDING SITE, designated SEQ ID:130, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of WAS protein family, member 3 (WASF3), a host gene which encodes a Protein that stimulates actin polymerization, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of WASF3 has been established by previous studies. The actin cytoskeleton plays critical roles in cell morphologic changes and motility. Rho family small GTPases such as Rho (see 165370), RAC (see 602048), and CDC42 (116952) organize the actin cytoskeleton. Other major players in actin-based motility are the 7 members of the ARP2/3 complex (see 604221). The Wiskott-Aldrich syndrome protein (WASP; 301000) and WASP-like (WASL; 605056) are among the downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. WASF1 (605035) is also involved in actin reorganization, but its expression is restricted to brain. By searching an EST database for homologs of WASF1 and by screening cDNA libraries, Suetsugu et al. (1999) identified WASF2 (605068) and WASF3, which they termed WAVE2 and WAVE3, respectively. The predicted 502-amino acid WASF3 protein shares 48% amino acid identity with WASF1. Northern blot analysis revealed that, like WASF1, WASF3 expression is strongest in brain, although weak expression was detected in kidney and liver. SDS-PAGE analysis showed that, like other WASP family members, WASF3 binds actin through its C-terminal verprolin homology (VPH) domain. Immunofluorescence microscopy demonstrated that ectopically expressed WASF3 induces abnormal actin clusters. These actin cluster formations were suppressed by deletion of the VPH domain of WASF3.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;     Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.:     Prediction of the coding sequences of unidentified human genes. XII.     The complete sequences of 100 new cDNA clones from brain which code     for large proteins in vitro. DNA Res. 5: 355-364, 1998. PubMed ID:     10048485 2. Suetsugu, S.; Miki, H.; Takenawa, T.: Identification of     two human WAVE/SCAR homologues as general actin regulatory molecules     which associate with the Arp2/3 complex. Biochem. Biophys. Res.     Commun. 260: 296-302, 1999.

Further studies establishing the function and utilities of WASF3 are found in John Hopkins OMIM database record ID 605068, and in references numbered 275-276 listed hereinbelow.

Reference is now made to WASF3 BINDING SITE. WAS protein family, member 3 (WASF3) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. WASF3 BINDING SITE is a host binding site found in the 3′ untranslated region of WASF3, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of WASF3 BINDING SITE, designated SEQ ID:130, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of WAS protein family, member 3 (WASF3), a host gene which encodes a Protein that stimulates actin polymerization, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of WASF3 has been established by previous studies. The actin cytoskeleton plays critical roles in cell morphologic changes and motility. Rho family small GTPases such as Rho (see 165370), RAC (see 602048), and CDC42 (116952) organize the actin cytoskeleton. Other major players in actin-based motility are the 7 members of the ARP2/3 complex (see 604221). The Wiskott-Aldrich syndrome protein (WASP; 301000) and WASP-like (WASL; 605056) are among the downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. WASF1 (605035) is also involved in actin reorganization, but its expression is restricted to brain. By searching an EST database for homologs of WASF1 and by screening cDNA libraries, Suetsugu et al. (1999) identified WASF2 (605068) and WASF3, which they termed WAVE2 and WAVE3, respectively. The predicted 502-amino acid WASF3 protein shares 48% amino acid identity with WASF1. Northern blot analysis revealed that, like WASF1, WASF3 expression is strongest in brain, although weak expression was detected in kidney and liver. SDS-PAGE analysis showed that, like other WASP family members, WASF3 binds actin through its C-terminal verprolin homology (VPH) domain. Immunofluorescence microscopy demonstrated that ectopically expressed WASF3 induces abnormal actin clusters. These actin cluster formations were suppressed by deletion of the VPH domain of WASF3.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;     Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.:     Prediction of the coding sequences of unidentified human genes. XII.     The complete sequences of 100 new cDNA clones from brain which code     for large proteins in vitro. DNA Res. 5: 355-364, 1998. PubMed ID:     10048485 2. Suetsugu, S.; Miki, H.; Takenawa, T.: Identification of     two human WAVE/SCAR homologues as general actin regulatory molecules     which associate with the Arp2/3 complex. Biochem. Biophys. Res.     Commun. 260: 296-302, 1999.

Further studies establishing the function and utilities of WASF3 are found in John Hopkins OMIM database record ID 605068, and in references numbered 275-276 listed hereinbelow.

Reference is now made to WASF3 BINDING SITE. WAS protein family, member 3 (WASF3) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. WASF3 BINDING SITE is a host binding site found in the 3′ untranslated region of WASF3, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of WASF3 BINDING SITE, designated SEQ ID:130, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of WAS protein family, member 3 (WASF3), a host gene which encodes a Protein that stimulates actin polymerization, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of WASF3 has been established by previous studies. The actin cytoskeleton plays critical roles in cell morphologic changes and motility. Rho family small GTPases such as Rho (see 165370), RAC (see 602048), and CDC42 (116952) organize the actin cytoskeleton. Other major players in actin-based motility are the 7 members of the ARP2/3 complex (see 604221). The Wiskott-Aldrich syndrome protein (WASP; 301000) and WASP-like (WASL; 605056) are among the downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. WASF1 (605035) is also involved in actin reorganization, but its expression is restricted to brain. By searching an EST database for homologs of WASF1 and by screening cDNA libraries, Suetsugu et al. (1999) identified WASF2 (605068) and WASF3, which they termed WAVE2 and WAVE3, respectively. The predicted 502-amino acid WASF3 protein shares 48% amino acid identity with WASF1. Northern blot analysis revealed that, like WASF1, WASF3 expression is strongest in brain, although weak expression was detected in kidney and liver. SDS-PAGE analysis showed that, like other WASP family members, WASF3 binds actin through its C-terminal verprolin homology (VPH) domain. Immunofluorescence microscopy demonstrated that ectopically expressed WASF3 induces abnormal actin clusters. These actin cluster formations were suppressed by deletion of the VPH domain of WASF3.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;     Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.:     Prediction of the coding sequences of unidentified human genes. XII.     The complete sequences of 100 new cDNA clones from brain which code     for large proteins in vitro. DNA Res. 5: 355-364, 1998. PubMed ID:     10048485 2. Suetsugu, S.; Miki, H.; Takenawa, T.: Identification of     two human WAVE/SCAR homologues as general actin regulatory molecules     which associate with the Arp2/3 complex. Biochem. Biophys. Res.     Commun. 260: 296-302, 1999.

Further studies establishing the function and utilities of WASF3 are found in John Hopkins OMIM database record ID 605068, and in references numbered 275-276 listed hereinbelow.

Reference is now made to WASF3 BINDING SITE. WAS protein family, member 3 (WASF3) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. WASF3 BINDING SITE is a host binding site found in the 3′ untranslated region of WASF3, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of WASF3 BINDING SITE, designated SEQ ID:130, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of WAS protein family, member 3 (WASF3), a host gene which encodes a Protein that stimulates actin polymerization, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of WASF3 has been established by previous studies. The actin cytoskeleton plays critical roles in cell morphologic changes and motility. Rho family small GTPases such as Rho (see 165370), RAC (see 602048), and CDC42 (116952) organize the actin cytoskeleton. Other major players in actin-based motility are the 7 members of the ARP2/3 complex (see 604221). The Wiskott-Aldrich syndrome protein (WASP; 301000) and WASP-like (WASL; 605056) are among the downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. WASF1 (605035) is also involved in actin reorganization, but its expression is restricted to brain. By searching an EST database for homologs of WASF1 and by screening cDNA libraries, Suetsugu et al. (1999) identified WASF2 (605068) and WASF3, which they termed WAVE2 and WAVE3, respectively. The predicted 502-amino acid WASF3 protein shares 48% amino acid identity with WASF1. Northern blot analysis revealed that, like WASF1, WASF3 expression is strongest in brain, although weak expression was detected in kidney and liver. SDS-PAGE analysis showed that, like other WASP family members, WASF3 binds actin through its C-terminal verprolin homology (VPH) domain. Immunofluorescence microscopy demonstrated that ectopically expressed WASF3 induces abnormal actin clusters. These actin cluster formations were suppressed by deletion of the VPH domain of WASF3.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;     Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.:     Prediction of the coding sequences of unidentified human genes. XII.     The complete sequences of 100 new cDNA clones from brain which code     for large proteins in vitro. DNA Res. 5: 355-364, 1998. PubMed ID:     10048485 2. Suetsugu, S.; Miki, H.; Takenawa, T.: Identification of     two human WAVE/SCAR homologues as general actin regulatory molecules     which associate with the Arp2/3 complex. Biochem. Biophys. Res.     Commun. 260: 296-302, 1999.

Further studies establishing the function and utilities of WASF3 are found in John Hopkins OMIM database record ID 605068, and in references numbered 275-276 listed hereinbelow.

Reference is now made to WASF3 BINDING SITE. WAS protein family, member 3 (WASF3) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. WASF3 BINDING SITE is a host binding site found in the 3′ untranslated region of WASF3, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of WASF3 BINDING SITE, designated SEQ ID:130, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of WAS protein family, member 3 (WASF3), a host gene which encodes a Protein that stimulates actin polymerization, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of WASF3 has been established by previous studies. The actin cytoskeleton plays critical roles in cell morphologic changes and motility. Rho family small GTPases such as Rho (see 165370), RAC (see 602048), and CDC42 (116952) organize the actin cytoskeleton. Other major players in actin-based motility are the 7 members of the ARP2/3 complex (see 604221). The Wiskott-Aldrich syndrome protein (WASP; 301000) and WASP-like (WASL; 605056) are among the downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. WASF1 (605035) is also involved in actin reorganization, but its expression is restricted to brain. By searching an EST database for homologs of WASF1 and by screening cDNA libraries, Suetsugu et al. (1999) identified WASF2 (605068) and WASF3, which they termed WAVE2 and WAVE3, respectively. The predicted 502-amino acid WASF3 protein shares 48% amino acid identity with WASF1. Northern blot analysis revealed that, like WASF1, WASF3 expression is strongest in brain, although weak expression was detected in kidney and liver. SDS-PAGE analysis showed that, like other WASP family members, WASF3 binds actin through its C-terminal verprolin homology (VPH) domain. Immunofluorescence microscopy demonstrated that ectopically expressed WASF3 induces abnormal actin clusters. These actin cluster formations were suppressed by deletion of the VPH domain of WASF3.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;     Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.:     Prediction of the coding sequences of unidentified human genes. XII.     The complete sequences of 100 new cDNA clones from brain which code     for large proteins in vitro. DNA Res. 5: 355-364, 1998. PubMed ID:     10048485 2. Suetsugu, S.; Miki, H.; Takenawa, T.: Identification of     two human WAVE/SCAR homologues as general actin regulatory molecules     which associate with the Arp2/3 complex. Biochem. Biophys. Res.     Commun. 260: 296-302, 1999.

Further studies establishing the function and utilities of WASF3 are found in John Hopkins OMIM database record ID 605068, and in references numbered 275-276 listed hereinbelow.

Reference is now made to WASF3 BINDING SITE. WAS protein family, member 3 (WASF3) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. WASF3 BINDING SITE is a host binding site found in the 3′ untranslated region of WASF3, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of WASF3 BINDING SITE, designated SEQ ID:130, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of WAS protein family, member 3 (WASF3), a host gene which encodes a Protein that stimulates actin polymerization, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of WASF3 has been established by previous studies. The actin cytoskeleton plays critical roles in cell morphologic changes and motility. Rho family small GTPases such as Rho (see 165370), RAC (see 602048), and CDC42 (116952) organize the actin cytoskeleton. Other major players in actin-based motility are the 7 members of the ARP2/3 complex (see 604221). The Wiskott-Aldrich syndrome protein (WASP; 301000) and WASP-like (WASL; 605056) are among the downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. WASF1 (605035) is also involved in actin reorganization, but its expression is restricted to brain. By searching an EST database for homologs of WASF1 and by screening cDNA libraries, Suetsugu et al. (1999) identified WASF2 (605068) and WASF3, which they termed WAVE2 and WAVE3, respectively. The predicted 502-amino acid WASF3 protein shares 48% amino acid identity with WASF1. Northern blot analysis revealed that, like WASF1, WASF3 expression is strongest in brain, although weak expression was detected in kidney and liver. SDS-PAGE analysis showed that, like other WASP family members, WASF3 binds actin through its C-terminal verprolin homology (VPH) domain. Immunofluorescence microscopy demonstrated that ectopically expressed WASF3 induces abnormal actin clusters. These actin cluster formations were suppressed by deletion of the VPH domain of WASF3.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;     Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.:     Prediction of the coding sequences of unidentified human genes. XII.     The complete sequences of 100 new cDNA clones from brain which code     for large proteins in vitro. DNA Res. 5: 355-364, 1998. PubMed ID:     10048485 2. Suetsugu, S.; Miki, H.; Takenawa, T.: Identification of     two human WAVE/SCAR homologues as general actin regulatory molecules     which associate with the Arp2/3 complex. Biochem. Biophys. Res.     Commun. 260: 296-302, 1999.

Further studies establishing the function and utilities of WASF3 are found in John Hopkins OMIM database record ID 605068, and in references numbered 275-276 listed hereinbelow.

Reference is now made to WASF3 BINDING SITE. WAS protein family, member 3 (WASF3) is a host target gene of VGAM23, corresponding to VGAM23-HOST-TARGET GENE of FIG. 23A. WASF3 BINDING SITE is a host binding site found in the 3′ untranslated region of WASF3, corresponding to HOST BINDING SITE of FIG. 23A. FIG. 23D illustrates the complementarity of the nucleotide sequence of WASF3 BINDING SITE, designated SEQ ID:130, to the nucleotide sequence of VGAM23 RNA of FIG. 23A, designated SEQ ID:122.

Yet a further function of VGAM23 is therefore inhibition of WAS protein family, member 3 (WASF3), a host gene which encodes a Protein that stimulates actin polymerization, as part of a novel viral mechanism used by Equine herpesvirus 2 for attacking a host. Accordingly, utilities of VGAM23 include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

The function of WASF3 has been established by previous studies. The actin cytoskeleton plays critical roles in cell morphologic changes and motility. Rho family small GTPases such as Rho (see 165370), RAC (see 602048), and CDC42 (116952) organize the actin cytoskeleton. Other major players in actin-based motility are the 7 members of the ARP2/3 complex (see 604221). The Wiskott-Aldrich syndrome protein (WASP; 301000) and WASP-like (WASL; 605056) are among the downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. WASF1 (605035) is also involved in actin reorganization, but its expression is restricted to brain. By searching an EST database for homologs of WASF1 and by screening cDNA libraries, Suetsugu et al. (1999) identified WASF2 (605068) and WASF3, which they termed WAVE2 and WAVE3, respectively. The predicted 502-amino acid WASF3 protein shares 48% amino acid identity with WASF1. Northern blot analysis revealed that, like WASF1, WASF3 expression is strongest in brain, although weak expression was detected in kidney and liver. SDS-PAGE analysis showed that, like other WASP family members, WASF3 binds actin through its C-terminal verprolin homology (VPH) domain. Immunofluorescence microscopy demonstrated that ectopically expressed WASF3 induces abnormal actin clusters. These actin cluster formations were suppressed by deletion of the VPH domain of WASF3.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   agase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Hirosawa, M.;     Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.:     Prediction of the coding sequences of unidentified human genes. XII.     The complete sequences of 100 new cDNA clones from brain which code     for large proteins in vitro. DNA Res. 5: 355-364, 1998. PubMed ID:     10048485 2. Suetsugu, S.; Miki, H.; Takenawa, T.: Identification of     two human WAVE/SCAR homologues as general actin regulatory molecules     which associate with the Arp2/3 complex. Biochem. Biophys. Res.     Commun. 260: 296-302, 1999.

Further studies establishing the function and utilities of WASF3 are found in John Hopkins OMIM database record ID 605068, and in references numbered 275-276 listed hereinbelow.

Reference is now made to FIG. 24A, which is a simplified diagram providing a conceptual explanation of the mode by which a novel bioinformatically detected viral gene, referred to here as Viral Genomic Address Messenger 24 (VGAM24) modulates expression of host target genes thereof, the function and utility of which host target genes is known in the art.

VGAM24 is a novel bioinformatically detected regulatory, non protein coding, viral micro RNA (miRNA) gene. The method by which VGAM24 was detected is described hereinabove with reference to FIGS. 2-8.

VGAM24 GENE is a viral gene contained in the genome of Melanoplus sanguinipes entomopoxvirus. VGAM24-HOST TARGET GENE is a human gene contained in the human genome.

VGAM24 GENE encodes a VGAM24 PRECURSOR RNA. Similar to other miRNA genes, and unlike most ordinary genes, the RNA transcribed by VGAM24, VGAM24 PRECURSOR RNA, does not encoded a protein.

VGAM24 PRECURSOR RNA folds onto itself, forming VGAM24 FOLDED PRECURSOR RNA. As FIG. 24 illustrates, VGAM24 FOLDED PRECURSOR RNA forms a ‘hairpin structure’, folding onto itself. As is well known in the art, this ‘hairpin structure’, is typical of RNA encoded by miRNA genes, and is due to the fact that the nucleotide sequence of the first half of the RNA encoded by a miRNA gene is an accurate or partial inversed-reversed sequence of the nucleotide sequence of the second half thereof. By “inversed-reversed” is meant a sequence which is reversed and wherein each nucleotide is replaced by a complimentary nucleotide, as is well known in the art (e.g. ATGGC is the inversed-reversed sequence of GCCAT).

An enzyme complex designated DICER COMPLEX, ‘dices’ the VGAM24 FOLDED PRECURSOR RNA into a single stranded ˜22 nt long RNA segment, designated VGAM24 RNA. As is known in the art, ‘dicing’ of a hairpin structured RNA precursor product into short a ˜22 nt RNA segment is catalyzed by an enzyme complex comprising an enzyme called Dicer together with other necessary proteins.

VGAM24-HOST TARGET GENE encodes a corresponding messenger RNA, designated VGAM24-HOST-TARGET RNA. VGAM24-HOST-TARGET RNA comprises three regions, as is typical of mRNA of a protein coding gene: a 5′ untranslated region, a protein coding region and a 3′ untranslated region, designated 5′UTR, PROTEIN CODING and 3′UTR respectively.

VGAM24 RNA binds complimentarily to a HOST BINDING SITE, located on an untranslated region of VGAM24-HOST-TARGET RNA. This complimentarily binding is due to the fact that the nucleotide sequence of VGAM24 RNA is an accurate or a partial inversed-reversed sequence of the nucleotide sequence of HOST BINDING SITE. It is appreciated that while FIG. 24A depicts the HOST BINDING SITE on the 3′UTR region, this is meant as an example only—the HOST BINDING SITE may be located on the 5′UTR region as well.

The complimentary binding of VGAM24 RNA to HOST BINDING SITE inhibits translation of VGAM24-HOST-TARGET RNA into VGAM24-HOST-TARGET PROTEIN. VGAM24-HOST-TARGET PROTEIN is therefore outlined by a broken line.

It is appreciated that VGAM24-HOST-TARGET GENE in fact represents a plurality of host target genes of VGAM24. The mRNA of each of this plurality of host target genes of VGAM24 comprises a HOST BINDING SITE, having a nucleotide sequence which is at least partly complementary to VGAM24 RNA, and which when bound by VGAM24 RNA causes inhibition of translation of one of a plurality of host target proteins of VGAM24. The plurality of host target genes of VGAM24 and their respective host binding sites, are described hereinbelow with reference to FIG. 24D.

It is appreciated by one skilled in the art that the mode of translational inhibition illustrated by FIG. 24A with specific reference to translational inhibition exerted by VGAM24 on one or more host target genes of VGAM24, is in fact common to other known miRNA genes. As mentioned hereinabove with reference to the background section, although a specific complimentary binding site has been demonstrated only for miRNA genes Lin-4 and Let-7, all other recently discovered miRNA genes are also believed by those skilled in the art to modulate expression of other genes by complimentary binding, although specific complimentary binding sites of these genes have not yet been found (Ruvkun G., ‘Perspective: Glimpses of a tiny RNA world’, Science 294, 779 (2001)).

It is further appreciated that a function of VGAM24 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM24 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

Reference is now made to FIG. 24B which shows the nucleotide sequence of VGAM24 PRECURSOR RNA of FIG. 24A, designated SEQ ID:135, and a probable nucleotide sequence of VGAM24 RNA of FIG. 24A, designated SEQ ID:136. The nucleotide sequence of SEQ ID:136, which is highly likely (over 28%) to be identical or highly similar to that of VGAM24, is marked by an underline within the sequence of VGAM24 PRECURSOR RNA.

Reference is now made to FIG. 24C, which shows the secondary folding of VGAM24 PRECURSOR RNA, forming a ‘hairpin structure’ designated VGAM24 FOLDED PRECURSOR RNA, both of FIG. 24A. A probable (>28%) nucleotide sequence of VGAM24 RNA, designated SEQ ID:136 of FIG. 24B, is marked by an underline on VGAM24 FOLDED PRECURSOR RNA. It is appreciated that the complimentary base-paring is not perfect, with ‘bulges’, as is well known in the art with respect to the RNA folding of all known miRNA genes.

Reference is now made to FIG. 24D, which is a table showing binding sites found in untranslated regions of a plurality of host target genes of VGAM24, each binding site corresponding to HOST BINDING SITE of FIG. 24A, and their complementarity to SEQ ID:136, which is highly likely (>28%) to be identical or highly similar to the nucleotide sequence of VGAM24 RNA of FIG. 24A.

As mentioned hereinabove with reference to FIG. 24A a function of VGAM24 is inhibition of expression of host target genes, as part of a novel viral mechanism of attacking a host. Accordingly, utilities of VGAM24 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus. It is appreciated that specific functions, and accordingly utilities, of VGAM24 correlate with, and may be deduced from, the identity of the host target genes which VGAM24 binds and inhibits, and the function of these host target genes, as elaborated hereinbelow.

Reference is now made to PDGFRA BINDING SITE. platelet-derived growth factor receptor, alpha polypeptide (PDGFRA) is a host target gene of VGAM24, corresponding to VGAM24-HOST TARGET GENE of FIG. 24A. PDGFRA BINDING SITE is a host binding site found in the 3′ untranslated region of PDGFRA, corresponding to HOST BINDING SITE of FIG. 24A. FIG. 24D illustrates the complementarity of the nucleotide sequence of PDGFRA BINDING SITE, designated SEQ ID:137, to the nucleotide sequence of VGAM24 RNA of FIG. 24A, designated SEQ ID:136.

A function of VGAM24 is therefore inhibition of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), a host gene which encodes a receptor that this receptor binds platelet-derived growth factor and has a tyrosine-protein kinase activity. and is associated with basal cell carcinomas, as part of a novel viral mechanism used by Melanoplus sanguinipes entomopoxvirus for attacking a host. Accordingly, utilities of VGAM24 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

The function of PDGFRA has been established by previous studies. Considerable insight into the role of the sonic hedgehog (600725) pathway in vertebrate development and human cancers came from the discovery that mutations in ‘patched’ (PTCH; 601309) are associated with basal cell nevus syndrome (BCNS; 109400), an autosomal dominant disorder combining developmental anomalies and tumors, particularly basal cell carcinomas (BCCs). Sporadic BCCs, the most common human cancer, consistently have abnormalities in the hedgehog pathway, and often mutations in PTCH. In addition, somatic mutations in ‘smoothened’ (SMOH; 601500), another protein in the hedgehog pathway, occur in sporadic BCCs. The downstream molecule GLI1 (165220) is known to mediate the biologic effect of the hedgehog pathway and is itself upregulated in all BCCs. Gli1 can drive the production of BCCs in the mouse when overexpressed in the epidermis. Xie et al. (2001) showed that GLI1 can activate PDGFR-alpha and that functional upregulation of PDGFR-alpha by GLI1 is accompanied by activation of the Ras-ERK pathway, which is associated with cell proliferation. The relevance of this mechanism in vivo is supported by a high level of expression of PDGFR-alpha in BCCs in mice and humans. From these and other observations, Xie et al. (2001) concluded that increased expression of the PDGFR-alpha gene may be an important mechanism by which mutations in the hedgehog pathway cause BCCs.

Animal model experiments lend further support to the function of PDGFRA. Klinghoffer et al. (2001) created 2 complementary lines of knockin mice in which the intracellular signaling domains of one PDGFR had been removed and replaced by those of the other PDGFR. While both lines demonstrated substantial rescue of normal development, substitution of the Pdgfrb signaling domains with those of Pdgfra resulted in varying degrees of vascular disease.

It is appreciated that the abovementioned animal model for PDGFRA is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Xie, J.; Aszterbaum, M.; Zhang, X.; Bonifas, J. M.; Zachary, C.;     Epstein, E.; McCormick, F.: A role of PDGFR-alpha in basal cell     carcinoma proliferation. Proc. Nat. Acad. Sci. 98: 9255-9259, 2001.     PubMed ID: 11481486 10. Klinghoffer, R. A.; Mueting-Nelsen, P. F.;     Faerman, A.; Shani, M.; Soriano, P.: The two PDGF receptors maintain     conserved signaling in vivo despite divergent embryological     functions. Molec. Cell 7: 343-354, 2001.

Further studies establishing the function and utilities of PDGFRA are found in John Hopkins OMIM database record ID 173490, and in references numbered 277-293 listed hereinbelow.

Reference is now made to PDGFRA BINDING SITE. platelet-derived growth factor receptor, alpha polypeptide (PDGFRA) is a host target gene of VGAM24, corresponding to VGAM24-HOST TARGET GENE of FIG. 24A. PDGFRA BINDING SITE is a host binding site found in the 3′ untranslated region of PDGFRA, corresponding to HOST BINDING SITE of FIG. 24A. FIG. 24D illustrates the complementarity of the nucleotide sequence of PDGFRA BINDING SITE, designated SEQ ID:137, to the nucleotide sequence of VGAM24 RNA of FIG. 24A, designated SEQ ID:136.

a function of VGAM24 is therefore inhibition of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), a host gene which encodes a receptor that this receptor binds platelet-derived growth factor and has a tyrosine-protein kinase activity. and is associated with basal cell carcinomas, as part of a novel viral mechanism used by Melanoplus sanguinipes entomopoxvirus for attacking a host. Accordingly, utilities of VGAM24 include diagnosis, prevention and treatment of viral infection by Melanoplus sanguinipes entomopoxvirus.

The function of PDGFRA has been established by previous studies. Considerable insight into the role of the sonic hedgehog (600725) pathway in vertebrate development and human cancers came from the discovery that mutations in ‘patched’ (PTCH; 601309) are associated with basal cell nevus syndrome (BCNS; 109400), an autosomal dominant disorder combining developmental anomalies and tumors, particularly basal cell carcinomas (BCCs). Sporadic BCCs, the most common human cancer, consistently have abnormalities in the hedgehog pathway, and often mutations in PTCH. In addition, somatic mutations in ‘smoothened’ (SMOH; 601500), another protein in the hedgehog pathway, occur in sporadic BCCs. The downstream molecule GLI1 (165220) is known to mediate the biologic effect of the hedgehog pathway and is itself upregulated in all BCCs. Gli1 can drive the production of BCCs in the mouse when overexpressed in the epidermis. Xie et al. (2001) showed that GLI1 can activate PDGFR-alpha and that functional upregulation of PDGFR-alpha by GLI1 is accompanied by activation of the Ras-ERK pathway, which is associated with cell proliferation. The relevance of this mechanism in vivo is supported by a high level of expression of PDGFR-alpha in BCCs in mice and humans. From these and other observations, Xie et al. (2001) concluded that increased expression of the PDGFR-alpha gene may be an important mechanism by which mutations in the hedgehog pathway cause BCCs.

Animal model experiments lend further support to the function of PDGFRA. Klinghoffer et al. (2001) created 2 complementary lines of knockin mice in which the intracellular signaling domains of one PDGFR had been removed and replaced by those of the other PDGFR. While both lines demonstrated substantial rescue of normal development, substitution of the Pdgfrb signaling domains with those of Pdgfra resulted in varying degrees of vascular disease.

It is appreciated that the abovementioned animal model for PDGFRA is acknowledged by those skilled in the art as a scientifically valid animal model, as can be further appreciated from the publications sited hereinbelow.

Full details of the abovementioned studies are described in the following publications, the disclosure of which are hereby incorporated by reference:

-   Xie, J.; Aszterbaum, M.; Zhang, X.; Bonifas, J. M.; Zachary, C.;     Epstein, E.; McCormick, F.: A role of PDGFR-alpha in basal cell     carcinoma proliferation. Proc. Nat. Acad. Sci. 98: 9255-9259, 2001.     PubMed ID: 11481486 10. Klinghoffer, R. A.; Mueting-Nelsen, P. F.;     Faerman, A.; Shani, M.; Soriano, P.: The two PDGF receptors maintain     conserved signaling in vivo despite divergent embryological     functions. Molec. Cell 7: 343-354, 2001.

Further studies establishing the function and utilities of PDGFRA are found in John Hopkins OMIM database record ID 173490, and in references numbered 277-293 listed hereinbelow.

Reference is now made to FIG. 3088, which is a simplified diagram describing a novel bioinformatically detected viral regulatory gene, referred to here as GR2, which encodes an ‘operon-like’ cluster of novel miRNA-like genes, each modulating expression of a plurality of target host genes, the function and utility of which target genes is known in the art.

GR2 GENE (Genomic Record 2 Gene) is a novel bioinformatically detected viral regulatory, non protein coding, RNA gene. The method by which GR2 was detected is described hereinabove with reference to FIGS. 2-8.

GR2 GENE encodes an RNA molecule, typically several hundred nucleotides long, designated GR2 PRECURSOR RNA.

GR2 PRECURSOR RNA folds spatially, as illustrated by GR2 FOLDED PRECURSOR RNA, into a plurality of what is known in the art as ‘hair-pin’ structures. The nucleotide sequence of GR2 PRECURSOR RNA comprises a plurality of segments, the first half of each such segment having a nucleotide sequence which is at least a partial inversed-reversed sequence of the second half thereof, thereby causing formation of a plurality of ‘hairpin’ structures, as is well known in the art.

GR2 FOLDED PRECURSOR RNA is naturally processed by cellular enzymatic activity, into at least 8 separate hairpin shaped RNA segments, each corresponding to VGAM PRECURSOR RNA, designated VGAM25 PRECURSOR, VGAM26 PRECURSOR, VGAM27 PRECURSOR, VGAM28 PRECURSOR, VGAM29 PRECURSOR, VGAM30 PRECURSOR, VGAM31 PRECURSOR and VGAM32 PRECURSOR respectively.

The above mentioned VGAM precursors, are diced by Dicer of FIG. 8, yielding short RNA segments of about 22 nucleotides in length, each corresponding to VGAM RNA of FIG. 8, designated VGAM25, VGAM26, VGAM27, VGAM28, VGAM29, VGAM30, VGAM31 and VGAM32 respectively.

VGAM25 binds complimentarily to a binding site located in an untranslated region of VGAM25-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 25A, thereby inhibiting translation of VGAM25-TARGET RNA into VGAM25-TARGET PROTEIN, both of FIG. 25A. The host target genes of VGAM25 and their respective functions, and accordingly the function and utility of VGAM25 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 25D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

VGAM26 binds complimentarily to a binding site located in an untranslated region of VGAM26-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 26A, thereby inhibiting translation of VGAM26-TARGET RNA into VGAM26-TARGET PROTEIN, both of FIG. 26A. The host target genes of VGAM26 and their respective functions, and accordingly the function and utility of VGAM26 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 26D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2

VGAM27 binds complimentarily to a binding site located in an untranslated region of VGAM27-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 27A, thereby inhibiting translation of VGAM27-TARGET RNA into VGAM27-TARGET PROTEIN, both of FIG. 27A. The host target genes of VGAM27 and their respective functions, and accordingly the function and utility of VGAM27 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 27D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2

VGAM28 binds complimentarily to a binding site located in an untranslated region of VGAM28-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 28A, thereby inhibiting translation of VGAM28-TARGET RNA into VGAM28-TARGET PROTEIN, both of FIG. 28A. The host target genes of VGAM28 and their respective functions, and accordingly the function and utility of VGAM28 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 28D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2.

VGAM29 binds complimentarily to a binding site located in an untranslated region of VGAM29-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 29A, thereby inhibiting translation of VGAM29-TARGET RNA into VGAM29-TARGET PROTEIN, both of FIG. 29A. The host target genes of VGAM29 and their respective functions, and accordingly the function and utility of VGAM29 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 29D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2

VGAM30 binds complimentarily to a binding site located in an untranslated region of VGAM30-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 30A, thereby inhibiting translation of VGAM30-TARGET RNA into VGAM30-TARGET PROTEIN, both of FIG. 30A. The host target genes of VGAM30 and their respective functions, and accordingly the function and utility of VGAM30 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 30D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2

VGAM31 binds complimentarily to a binding site located in an untranslated region of VGAM31-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 31A, thereby inhibiting translation of VGAM31-TARGET RNA into VGAM31-TARGET PROTEIN, both of FIG. 31A. The host target genes of VGAM31 and their respective functions, and accordingly the function and utility of VGAM31 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 31D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2

VGAM32 binds complimentarily to a binding site located in an untranslated region of VGAM32-TARGET RNA, which binding site corresponds to HOST BINDING SITE of FIG. 32A, thereby inhibiting translation of VGAM32-TARGET RNA into VGAM32-TARGET PROTEIN, both of FIG. 32A. The host target genes of VGAM32 and their respective functions, and accordingly the function and utility of VGAM32 as part of a novel viral mechanism of attacking a host are described hereinabove with reference to FIG. 32D, and include diagnosis, prevention and treatment of viral infection by Equine herpesvirus 2

Additional 1046 novel viral genes disclosed by the present invention are described with reference to FIGS. 25 through 1000 and 3088 through 3308, which Figs. and description thereof is enclosed in computer readable form.

It is appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described hereinabove. Rather the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove as well as variations and modifications which would occur to persons skilled in the art upon reading the specifications and which are not in the prior art.

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What is claimed is:
 1. A bioinformatically detectable novel viral gene encoding substantially pure nucleic acid wherein: a) RNA encoded by said bioinformatically detectable novel viral gene is about 18 to about 24 nucleotides in length, and originates from an RNA precursor, which RNA precursor is about 50 to about 120 nucleotides in length; b) a nucleotide sequence of a first half of said RNA precursor is a partial inversed-reversed sequence of a nucleotide sequence of a second half thereof; c) a nucleotide sequence of said RNA encoded by said novel viral gene is a partial inversed-reversed sequence of a nucleotide sequence of a binding site associated with at least one host target gene; and d) a function of said novel viral gene is bioinformatically deducible.
 2. A bioinformatically detectable novel viral gene encoding substantially pure DNA wherein: a) RNA encoded by said bioninformatically detectable novel viral gene comprises a plurality of RNA sections, each of said RNA sections being about 50 to about 120 nucleotides in length, and comprising an RNA segment, which RNA segment is about 18 to about 24 nucleotides in length; b) a nucleotide sequence of a first half of each of said RNA sections encoded by said novel gene is a partial inversed-reversed sequence of nucleotide sequence of a second half thereof; c) a nucleotide sequence of each of said RNA segments encoded by said novel gene is a partial inversed-reversed sequence of the nucleotide sequence of a binding site associated with at least one target gene; and d) a function of said novel gene is bioinformatically deducible from the following data elements: said nucleotide sequence of said RNA encoded by said novel gene, a nucleotide sequence of said at least one target gene, and function of said at least one target gene.
 3. A bioinformatically detectable novel viral gene encoding substantially pure DNA wherein: a) RNA encoded by said bioinformatically detectable novel gene is about 18 to about 24 nucleotides in length, and originates from an RNA precursor, which RNA precursor is about 50 to about 120 nucleotides in length; b) a nucleotide sequence of a first half of said RNA precursor is a partial inversed-reversed sequence of a nucleotide sequence of a second half thereof; c) a nucleotide sequence of said RNA encoded by said novel gene is a partial inversed-reversed sequence of a nucleotide sequence of a binding site associated with at least one target gene; d) a function of said novel gene is modulation of expression of said at least one target gene; and e) said at least one target gene does not encode a protein.
 6. A bioinformatically detectable novel gene according to claim 1 and wherein said function of said novel gene is bioinformatically deducible from the following data elements: a) said nucleotide sequence of said RNA encoded by said bioinformatically detectable novel gene, b) a nucleotide sequence of said at least one target gene; and c) a function of said at least one target gene.
 7. A bioinformatically detectable novel gene according to claim 1 and wherein said RNA encoded by said novel gene complementarily binds said binding site associated with said at least one target gene, thereby modulating expression of said at least one target gene.
 8. A bioinformatically detectable novel gene according to claim 1 and wherein: said binding site associated with at least one target gene is located in an untranslated region of RNA encoded by said at least one target gene.
 9. A bioinformatically detectable novel gene according to claim 7 and wherein: said function of said novel gene is selective inhibition of translation of said at least one target gene, which selective inhibition comprises complementary hybridization of said RNA encoded by said novel gene to said binding site.
 10. A vector comprising the DNA of claim
 1. 11. A method of selectively inhibiting translation of at least one gene, comprising introducing the vector of claim 10 into a cell.
 12. A method according to claim 11 and wherein said introducing comprises utilizing RNAi pathway.
 13. A gene expression inhibition system comprising: a) the vector of claim 10; and b) a vector inserter, functional to insert said vector of claim 10 into a cell, thereby selectively inhibiting translation of at least one gene.
 14. A probe comprising the DNA of claim
 1. 15. A method of selectively detecting expression of at least one gene, comprising using the probe of claim
 14. 16. A gene expression detection system comprising: a) the probe of claim 14; and b) a gene expression detector functional to selectively detect expression of at least one gene.
 17. An anti-viral substance capable of neutralizing said RNA of claim
 1. 18. A substance according to claim 17 and wherein said neutralizing comprises complementarily binding said RNA.
 19. A substance according to claim 17 and wherein said neutralizing comprises immunologically neutralizing.
 20. A method for anti-viral treatment comprising neutralizing said RNA of claim
 21. A method according to claim 20 and wherein said neutralizing comprises: a) synthesizing a complementary nucleic acid molecule, a nucleic sequence of which complementary nucleic acid molecule is a partial inversed-reversed sequence of said RNA; and b) transfecting host cells with said complementary nucleic acid molecule, thereby complementarily binding said RNA.
 22. A method according to claim 20 and wherein said neutralizing comprises immunologically neutralizing. 